2-substituted-4-nitrogen heterocycles as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of CCR3 of formula (I):or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma and other allergic diseases.

This application claims the benefit of U.S. Provisional Application No.60/112,716, filed Dec. 18, 1998.

FIELD OF THE INVENTION

This invention relates generally to modulators of chemokine receptoractivity, pharmaceutical compositions containing the same, and methodsof using the same as agents for treatment and prevention of asthma andallergic diseases, as well as autoimmune pathologies such as rheumatoidarthritis and atherosclerosis.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338,436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are twomajor classes of chemokines, CXC and CC, depending on whether the firsttwo cysteines in the amino acid sequence are separated by a single aminoacid (CXC) or are adjacent (CC). The CXC chemokines, such asinterleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1a, MIP-1b, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1 and -2) arechemotactic for, among other cell types, macrophages, T lymphocytes,eosinophils, dendritic cells, and basophils. There also exist thechemokines lymphotactin-1, lymphotactin-2 (both C chemokines), andfractalkine (a CXXXC chemokine) that do not fall into either of themajor chemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal through theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration. There are at least tenhuman chemokine receptors that bind or respond to CC chemokines with thefollowing characteristic patterns: CCR-1 (or “CKR-1” or “CC-CKR-1”)[MIP-1a, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425(1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A andCCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2,MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91,2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3(or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster,New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or “CKR-4” or “CC-CKR-4”)[TARC, MIP-1a, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270,19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998));CCR-5 (or “CKR-5” OR “CC-CKR-5”) [MIP-1a, RANTES, MIP-1b] (Sanson, etal., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or “CKR-6” or“CC-CKR-6”) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898(1997)); CCR-7 (or “CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J.Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or “CKR-8” or “CC-CKR-8”)[I-309, TARC, MIP-1b] (Napolitano et al., J. Immunol., 157, 2759-2763(1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); andCCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3] (Bonini et al, DNAand Cell Biol., 16, 1249-1256 (1997)).

In addition to the mammalian chemokine receptors, mammaliancytomegaloviruses, herpesviruses and poxviruses have been shown toexpress, in infected cells, proteins with the binding properties ofchemokine receptors (reviewed by Wells and Schwartz, Curr. Opin.Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES andMCP-3, can cause rapid mobilization of calcium via these virally encodedreceptors. Receptor expression may be permissive for infection byallowing for the subversion of normal immune system surveillance andresponse to infection. Additionally, human chemokine receptors, such asCXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for theinfection of mammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

Chemokine receptors have been implicated as being important mediators ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Forexample, the chemokine receptor CCR-3 plays a pivotal role in attractingeosinophils to sites of allergic inflammation and in subsequentlyactivating these cells. The chemokine ligands for CCR-3 induce a rapidincrease in intracellular calcium concentration, increased expression ofcellular adhesion molecules, cellular degranulation, and the promotionof eosinophil migration. Accordingly, agents which modulate chemokinereceptors would be useful in such disorders and diseases. In addition,agents which modulate chemokine receptors would also be useful ininfectious diseases such as by blocking infection of CCR3 expressingcells by HIV or in preventing the manipulation of immune cellularresponses by viruses such as cytomegaloviruses.

A substantial body of art has accumulated over the past several decadeswith respect to substituted piperidines and pyrrolidines. Thesecompounds have implicated in the treatment of a variety of disorders.

WO 98/25604 describes spiro-substituted azacycles which are useful asmodulators of chemokine receptors:

wherein R₁ is C₁₋₆ alkyl, optionally substituted with functional groupssuch as —NR⁸CONHR⁹, and R⁸ and R⁹ may be phenyl further substituted withhydroxy, alkyl, cyano, halo and haloalkyl. Such Spiro compounds are notconsidered part of the present invention.

U.S. Pat. No. 5,264,420 discloses fibrinogen receptor antagonistscomprising carbon-linked disubstituted heterocyclic amines as acomponent of a multiamidic moiety:

These compounds can be distinguished from the present invention by thenature of the multiamidic moiety.

WO 96/31111 discloses farnesyl protein transferase inhibitors where R²can be C₁₋₆ alkyl, optionally substituted with functional groups such as—NR⁸COR⁹ and —NR⁸CONR⁹R¹⁰ wherein R⁹ may be phenyl which can havefurther substitution.

Such compounds which contain tri-substituted ketones are notcontemplated by the present invention.

WO 96/11200 discloses purine and guanine compounds as inhibitors ofpurine nucleoside phosphorylase:

wherein R⁴ can be C₁₋₆ alkyl, optionally substituted with functionalgroups such as —NHCONHAr where Ar may be phenyl further substituted.Such guanines and purines as substituents on heterocycles are notconsidered part of the present invention.

Compounds known in the art are readily distinguished structurally byeither the nature or location of the linking chain, or other possiblesubstitution patterns of the present invention. The prior art does notdisclose nor suggest the unique combination of structural fragmentswhich embody these novel heterocycles as having activity toward thechemokine receptors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novelagonists or antagonists of CCR-3, or pharmaceutically acceptable saltsor prodrugs thereof.

It is another object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

It is another object of the present invention to provide a method fortreating allergic disorders comprising administering to a host in needof such treatment a therapeutically effective amount of at least one ofthe compounds of the present invention or a pharmaceutically acceptablesalt or prodrug form thereof.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, whereinJ, K, L, M, R¹, R², R³, and R⁴ are defined below are effectivemodulators of chemokine activity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Thus, in a first embodiment, the present invention provides novelcompounds of formula I:

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:

J is selected from CH₂ and CHR⁵;

K and L are independently selected from CR⁵R⁶ and CR⁶R⁶;

M, at each occurrence, is selected from CR⁵R⁶ and CR⁶R⁶;

with the proviso that at least one of J, K, L, or M contains an R⁵;

X is selected from (CR⁷′R⁷′)_(q)—S—(CR⁷′R⁷′)_(q),(CR⁷′R⁷′)_(q)—O—(CR⁷′R⁷′)_(q), (CR⁷′R⁷′)_(q)—NR⁷—(CR⁷′R⁷′)_(q),(CR⁷′R⁷′)_(r)—C(O)—(CR⁷′R⁷′)_(q), C₁₋₆ alkylene substituted with 0-5 R⁷,C₂₋₁₀ alkenylene substituted with 0-5 R⁷, C₂₋₁₀ alkynylene substitutedwith 0-5 R⁷, and (CR⁷R⁷)_(t)—A—(CR⁷R⁷)_(t) substituted with 0-3 R⁸;

with the proviso that when R⁷ or R⁷′ is bonded to the same carbon as Y,R⁷ is not halogen, cyano, or bonded through a heteroatom;

A is C₃₋₆ carbocyclic residue;

Y is selected from NR¹¹C(═O)NR¹¹, NR¹¹C(═S)NR¹¹, NR¹¹C(═NR^(a))NR¹¹,NR¹¹C(═CHCN)NR¹¹, NR¹¹C(═CHNO₂)NR¹¹, NR¹¹C(═C(CN)₂)NR¹¹, NR¹¹, C(O),S(O)₂NR¹¹, NR¹¹S(O)₂, NR¹¹S(O)₂NR¹¹, C(O)NR¹¹, NR¹¹C(O), NR¹¹C(O)O,OC(O)NR¹¹, and S(O)_(p);

R^(a) is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, O—C₁₋₆alkyl, and (CH₂)_(w)phenyl;

R¹ is selected from a (CR¹′R¹″)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R⁹ and a (CR¹′R¹″)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R⁹;

R¹′ and R¹″, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;

R², at each occurrence, is selected from H, C₁₋₈ alkyl,(CR²′R²″)_(q)NR^(12a)R^(12a)′, (CR²′R²″)_(w)OH,(CR²′R²″)_(w)O(CR²′R²″)_(r)R^(12d), (CR²′R²″)_(q)SH, (CR²′R²″)_(r)C(O)H,(CR²′R²″)_(q)S(CR²′R²″)_(r)R^(12d), (CR²′R²″)_(r)C(O)OH,(CR²′R²″)_(r)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)NR^(12a)C(NR^(a))NR^(12a)R^(12a)′,(CR²′R²″)_(r)C(NR^(a))NR^(12a)R^(12a′, (CR) ²′R²″)_(r)C(NR^(a))R^(12b),(CR²′R²″)_(r)C(O)NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(r)C(O)O(CR²′R²″)_(r)R^(12d),(CR²′R²″)_(w)OC(O)(CR²′R²′)_(r)R^(12b),(CR²′R²″)_(w)S(O)_(p)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)S(O)₂NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)S(O)₂(CR²′R²″)_(r)R^(12b), C₁₋₆ haloalkyl, C₂₋₈alkenyl substituted with 0-3 R^(12c), C₂₋₈ alkynyl substituted with 0-3R^(12c), a (CR²′R²″)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(12c), and a (CH₂)_(r)—5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(12c);

alternatively, R² is an amino acid residue;

R²′ and R²″, at each occurrence, are selected from H, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CF₂)_(r)CF₃, (CH₂)_(r)CN, (CH₂)_(r)NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)NR^(2a)R^(2a), (CH₂)_(r)OH, (CH₂)_(r)OR^(2b), (CH₂)_(r)SH,(CH₂)_(r)SR^(2b), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(2b),(CH₂)_(r)C(O)NR^(2a)R^(2a)′, (CH₂)_(r)NR^(2d)C(O)R^(2a),(CH₂)_(r)C(O)OR^(2b), (CH₂)_(r)OC(O)R^(2b), (CH₂)_(r)S(O)_(p)R^(2b),(CH₂)_(r)S(O)₂NR^(2a)R^(2a)′, (CH₂)NR^(2d)S(O)₂R^(2b), C₁₋₆ haloalkyl, a(CR²′R²″)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(2c), anda (CH₂)_(r)—5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(2c);

R^(2a) and R^(2a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(2c);

R^(2b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(2c);

R^(2c), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(2d)R^(2d), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(2b),(CH₂)_(r)C(O)NR^(2d)R^(2d), (CH₂)_(r)NR^(2d)C(O)R^(7a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(2b),(CH₂)_(r)C(═NR^(2d))NR^(2d)R^(2d), (CH₂)_(r)S(O)_(p)R^(2d),(CH₂)_(r)NHC(═NR^(2d))NR^(2d)R^(2d), (CH₂)_(r)S(O)₂NR^(2d)R^(2d),(CH₂)_(r)NR^(2d)S(O)₂R^(2b), and (CH₂)_(r)phenyl substituted with 0-3R^(9e);

R^(2d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R³ is selected from HF C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, (CF₂)_(r)CF₃, (CH₂)_(q)NR^(3a)R^(3a)′, (CH₂)_(q)OH,(CH₂)_(q)OR^(3b), (CH₂)_(q)SH, (CH₂)_(q)SR^(3b), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(3b), (CH₂)_(r)C(O)NR^(3a)R^(3a)′,(CH₂)_(q)NR^(3d)C(O)R^(3a), (CH₂)_(r)C(O)OR^(3b), (CH₂)_(q)OC(O)R^(3b),(CH₂)_(r)S(O)_(p)R^(3b), (CH₂)_(r)S(O)₂ NR^(3a)R^(3a)′,(CH₂)_(q)NR^(3d)S(O)₂R^(3b), and (CH₂)_(r)-phenyl substituted with 0-3R^(3c);

R^(3a) and R^(3a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(3c);

R^(3b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(3c);

R^(3c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(3d)R^(3d);

R^(3d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R⁴ is absent, taken with the nitrogen to which it is attached to form anN-oxide, or selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),(CH₂)_(q)C(O)NR^(4a)R^(4a)′, (CH₂)_(q)C(O)OR^(4b), and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4c);

R^(4a) and R^(4a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;

R^(4b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,(CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, and phenyl;

R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4a)R^(4a)′, and (CH₂)_(r)phenyl;

R⁵ is selected from a (CR⁵′R⁵″)_(t)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R¹⁰ and a (CR⁵′R⁵″)_(t)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R¹⁰;

R⁵′ and R⁵″, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl;

alternatively, R⁵ and R⁶ join to form a 5, 6, or 7-membered spirocycle,containing 0-3 heteroatoms selected from N, O, and S, substituted with0-3 R¹⁶;

R⁶, at each occurrence, is selected from H, C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃, CN,(CH₂)_(r)NR^(6a)R^(6a)′, (CH₂)_(r)OH, (CH₂)_(r)OR^(6b), (CH₂)_(r)SH,(CH₂)_(r)SR^(6b), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(6b),(CH₂)_(r)C(O)NR^(6a)R^(6a)′, (CH₂)_(r)NR^(6d)C(O)R^(6a),(CH₂)_(r)C(O)OR^(6b), (CH₂)_(r)OC(O)R^(6b), (CH₂)_(r)S(O)_(p)R^(6b),(CH₂)_(r)S(O)₂NR^(6a)R^(6a)′, (CH₂)_(r)NR^(6d)S(O)₂R^(6b), and(CH₂)_(t)phenyl substituted with 0-3 R^(6c);

R^(6a) and R^(6a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c);

R^(6b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(6c);

R^(6c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(6d)R^(6d);

R^(6d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, F, Cl, Br, I, (CH₂)_(r)OH, (CH₂)_(r)SH, (CH₂)_(r)OR^(7d),(CH₂)_(r)SR^(7d), (CH₂)_(r)NR^(7a)R^(7a)′, C₁₋₆ haloalkyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(7c);

R^(7a) and R^(7a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(7e);

R^(7b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ cycloalkyl, and phenyl substituted with0-3 R^(7e);

R^(7c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₆ alkyl, OH, SH, (CH₂)_(r)SC₁₋₆ alkyl,(CH₂)_(r)NR^(7d)R^(7d), C(O)C₁₋₆ alkyl, and (CH₂)_(r)phenyl;

R^(7d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, C₃₋₆cycloalkyl, and phenyl;

R⁷′, at each occurrence, is selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)SH, (CH₂)_(q)OR^(7b),(CH₂)_(q)SR^(7b), (CH₂)_(q)NR^(7a)R^(7a)′, (CH₂)_(r)C(O)OH, C₁₋₆haloalkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(7c);

R⁸, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(8a)R^(8a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(8d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(8d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(8b),(CHR′)_(r)C(O)NR^(8a)R^(8a)′, (CHR′)_(r)NR^(8f)C(O)(CHR′)_(r)R^(8b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(8d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(8b),(CHR′)_(r)C(═NNR^(8f))NR^(8a)R^(8a)′,(CHR′)_(r)NHC(═NR^(8f))NR^(8f)R^(8f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(8b), (CHR′)_(r)S(O)₂NR^(8a)R^(8a)′,(CHR′)_(r)NR^(8f)S(O)₂(CHR′)_(r)R^(8b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(8e);

R′, at each occurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substitutedwith R^(8e);

R^(8a) and R^(8a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(8e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(8e);

R^(8b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(8e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(8e);

R^(8d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₆ alkyl substituted with 0-3 R^(8e), a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(8e), and a (CH₂)_(r)5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(8e);

R^(8e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br; I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(8f)R^(8f), and (CH₂)_(r)phenyl;

R^(8f), at each occurrence, is selected from H, C₁₋₅ alkyl, C₃₋₆cycloalkyl, and phenyl;

R⁹, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(9a)R^(9a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(9d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(9d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(9b),(CHR′)_(r)C(O)NR^(9a)R^(9a)′, (CHR′)_(r)NR^(9f)C(O)(CHR′)_(r)R^(9b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(9d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(9b),(CHR′)_(r)C(═NR^(9f))NR^(9a)R^(9a)′,(CHR′)_(r)NHC(═NR^(9f))NR^(9f)R^(9f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(9b), (CHR′)_(r)S(O)₂NR^(9a)R^(9a)′,(CHR′)_(r)NR^(9f)S(O)₂(CHR′)_(r)R^(9b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(9e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(9e);

R^(9a) and R^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(9e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(9e);

R^(9b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(9e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(9e);

R^(9d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₆ alkyl substituted with 0-3 R^(9e), a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(9e), and a (CH₂)r5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(9e);

R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;

R^(9f), at each occurrence, is selected from H, C₁₋₅ alkyl, C₃₋₆cycloalkyl, and phenyl;

R¹⁰, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(10a)R^(10a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(10d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(10d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(10b),(CHR′)_(r)C(O)NR^(10a)R^(10a)′, (CHR′)_(r)NR^(10f)C(O)(CHR′)_(r)R^(10b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(10d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(10b),(CHR′)_(r)C(═NR^(10f))NR^(10a)R^(10a)′,(CHR′)_(r)NHC(═NR^(10f))NR^(10f)R^(10f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(10b), (CHR′)_(r)S(O)₂NR^(10a)R^(10a)′,(CHR′)_(r)NR^(10f)S(O)₂(CHR′)_(r)R^(10b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(10e);

R^(10a) and R^(10a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(10e);

R^(10b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(10e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(10e);

R^(10d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(10e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(10e), and a (CH₂)_(r)5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(10e);

R¹⁰e, at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl;

R^(10f), at each occurrence, is selected from H, C₁₋₅ alkyl, C₃₋₆cycloalkyl, and phenyl;

R¹¹, at each occurrence is selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(11a);

R^(11a), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(11b)R^(11b), (CH₂)_(r)OH, (CH₂)_(r)OR^(11c),(CH₂)_(r)SH, (CH₂)_(r)SR^(11c), (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11b)R^(11b), (CH₂)_(r)NR^(11b)C(O)R^(11b),(CH₂)_(r)C(O)OR^(11b), (CH₂)_(r)OC(O)R^(11c),(CH₂)_(r)CH(═NR^(11b))NR^(11b)R^(11b),(CH₂)_(r)NHC(═NR^(11b))NR^(11b)R^(11b), (CH₂)_(r)S(O)_(p)R^(11c),(CH₂)_(r)S(O)₂NR^(11b)R^(11b), (CH₂)_(r)NR^(11b)S(O)₂R^(11c), and(CH₂)_(r)phenyl;

R^(11b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R^(11c), at each occurrence, is selected from C₁₋₅ alkyl, C₃₋₆cycloalkyl, and phenyl;

R^(12a) and R^(12a)′, at each occurrence, are selected from H, C₁₋₆alkyl substituted with 0-3 R^(12e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(12e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(12e);

R^(12b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(12e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(12e);

R^(12c), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(12f)R^(12f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(12b),(CH₂)_(r)C(O)NR^(12f)R^(12f), (CH₂)_(r)NR^(12f)C(O)R^(12a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(12b),(CH₂)_(r)C(═NR^(12f))NR^(12f)R^(12f), (CH₂)_(r)S(O)_(p)R^(12b),(CH₂)_(r)NHC(═NR^(12f))NR^(12f)R^(12f), (CH₂)_(r)S(O)₂NR^(12f)R^(12f),(CH₂)_(r)NR^(12f)S(O)₂R^(12b), and (CH₂)_(r)phenyl substituted with 0-3R^(12e);

R^(12d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(12e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(12e), and a (CH₂)_(r)5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(12e);

R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;

R^(12f), at each occurrence, is selected from H, C₁₋₅ alkyl, C₃₋₆cycloalkyl, and phenyl;

w is selected from 2, 3, 4, and 5;

v is selected from 0, 1 and 2;

t is selected from 0, 1 and 2;

r is selected from 0, 1, 2, 3, 4, and 5,

q is selected from 1, 2, 3, 4, and 5; and

p is selected from 1, 2, and 3.

In certain embodiments, the present invention provides compound novelcompounds of formula I, wherein:

R³ is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl;

R⁴ is absent, taken with the nitrogen to which it is attached to form anN-oxide, or selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)-phenyl substituted with 0-3 R^(4c);

R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, CF₃,(CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH;

R⁶, at each occurrence, is selected from H, C₁₋₄ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, (CF₂)_(r)CF₃, (CH₂)_(r)OH, (CH₂)_(r)OR^(6b), and(CH₂)_(t)phenyl substituted with 0-3 R^(6c);

R^(6c), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(6d)R^(6d);

R^(6d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl;

q is selected from 1, 2, and 3;

r is selected from 0, 1, 2, and 3; and

v is selected from 0, and 1.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein:

R², at each occurrence, is selected from H, C₁₋₈ alkyl,(CH₂)_(r)C(O)R^(12b), (CH₂)_(r)C(O)NR^(12a)R^(12a)′,(CH₂)_(r)C(O)OR^(12d), (CH₂)_(r)S(O)_(p)R^(12b),(CH₂)_(r)S(O)₂NR^(12a)R^(12a)′, (CR²′R²″)_(w)NR^(12s)C(NR^(a))NR^(12a)R^(12a)′, (CR²′R²″)_(r)C(NR^(a))NR^(12a)R^(12a)′,(CR²′R²″)_(r)C(NR^(a))R^(12b), a (CH₂)_(r)-carbocyclic residuesubstituted with 0-3 R^(12c), wherein the carbocyclic residue isselected from:

phenyl, C₃₋₆ cycloalkyl, napthyl, and adamantyl; and a (CH₂)_(r)-5-6membered heterocyclic system substituted with 0-2 R^(12c), wherein theheterocyclic system is selected from:

pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,isoidolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;

alternatively, R² is an amino acid residue;

R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, F, Cl, Br, I, (CH₂)_(r)OH, (CH₂)_(r)OR^(7d),(CH₂)_(r)NR^(7a)R^(7a)′, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)-phenylsubstituted with 0-3 R^(7e);

R^(7a) and R^(7a), at each occurrence, are selected from H, C₁₋₆ alkyl;

R^(7d), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

R^(7e) is selected from H and C₁₋₆ alkyl;

R⁷′ is H;

R¹¹, at each occurrence is selected from H, and C₁₋₈ alkyl;

R^(12a) and R^(12a)′, at each occurrence, are selected from H, C₁₋₆alkyl, and phenyl with 0-3 R^(12e);

R^(12b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(12e);

R^(12c), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(12f)R^(12f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)C(O)R^(12b), (CH₂)_(r)C(O)NR^(12f)R^(12f),(CH₂)_(r)NR^(12f)C(O)R^(12a), (CH₂)_(r)S(O)₂NR^(12f)R^(12f),(CH₂)_(r)NR^(12f)S(O)₂R^(12b), and (CH₂)_(r)phenyl substituted with 0-3R^(12e);

R^(12e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, (CH₂)_(r)NR^(12f)R^(12f), and(CH₂)_(r)phenyl; and

R^(12f), at each occurrence, is selected from H, C₁₋₅ alkyl, C₃₋₆cycloalkyl, and phenyl.

In certain embodiments, the present invention provides compounds offormula I, wherein:

A is selected from phenyl, cyclohexyl, cyclopentyl, and cyclopropyl;

R¹ is selected from a (CR¹′H)_(r)-carbocyclic residue substituted with0-5 R⁹, wherein the carbocyclic residue is selected from phenyl, C₃₋₆cycloalkyl, napthyl, and adamantyl; and a (CR¹′H)_(r)-heterocyclicsystem substituted with 0-3 R⁹, wherein the heterocyclic system isselected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and

R⁵ is selected from (CR⁵′H)_(t)-phenyl substituted with 0-5 R¹⁰; and a(CR⁵′H)_(t)-heterocyclic system substituted with 0-3 R¹⁰, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl.

In certain embodiments, the present invention provides compounds offormula I, wherein:

X is selected from C₁₋₅ alkylene substituted with 0-5 R⁷, C₂₋₁₀, C₂₋₆alkynylene substituted with 0-5 R⁷, and (CR⁷R⁷)_(t)—A—(CR⁷R⁷)_(t)substituted with 0-4 R⁸; and

Y is selected from NHC(═O)NH, NHC(═S)NH, NHC(═NR^(a))NH, NHC(═CHCN)NH,NHC(═CHNO₂)NH, NHC(═C(CN)₂)NH, C(O)NH, and NHC(O).

In certain embodiments, the present invention provides compounds offormula I-i:

wherein:

R⁸, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(8a)R^(8a)′, NO₂, CN, OH,(CH₂)_(r)OR^(8d), (CH₂)_(r)C(O)R^(8b), (CH₂)_(r)C(O)NR^(8a)R^(8a)′,(CH₂)_(r)NR^(8f)C(O)R^(8b), (CH₂)_(r)S(O)_(p)R^(8b),(CH₂)_(r)S(O)₂NR^(8a)R^(8a)′, (CH₂)_(r)NR^(8f)S(O)₂R^(8b), and(CH₂)_(r)phenyl substituted with 0-3 R^(8e);

R^(8a) and R^(8a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(8e);

R^(8b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(8e);

R^(8d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(8e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(8f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

R¹⁰, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(10a)R^(10a)′, NO₂, CN, OH,(CH₂)_(r)OR^(10d), (CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10a)R^(10a)′,(CH₂)_(r)NR^(10f)C(O)R^(10b), (CH₂)_(r)S(O)_(p)R^(10b),(CH₂)_(r)S(O)₂NR^(10a)R^(10a)′, (CH₂)_(r)NR^(10f)S(O)₂R^(10b), and(CH₂)_(r)phenyl substituted with 0-3 R^(10e);

R^(10a) and R^(10a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(10e);

R^(10b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(10e);

R^(10d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(10e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(10f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

In certain embodiments of formula I-i, the present invention providesnovel compounds, wherein:

R⁵ is CH₂phenyl substituted with 0-3 R¹⁰;

K is selected from CH₂ and CHR⁵;

L is selected from CH₂ and CHR⁵;

M is selected from CH₂ and CHR⁵;

R⁹, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(9a)R^(9a)′, NO₂, CN, OH,(CH₂)_(r)OR^(9d), (CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9a)R^(9a)′,(CH₂)_(r)NR^(9f)C(O)R^(9b), (CH₂)_(r)S(O)_(p)R^(9b),(CH₂)_(r)S(O)₂NR^(9a)R^(9a)′, (CH₂)_(r)NR^(9f)S(O)₂R^(9b),(CH₂)_(r)phenyl substituted with 0-3 R^(9e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(9e);

R^(9a) and R^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e);

R^(9b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e);

R^(9d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(9f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

In certain embodiments of formula I-i, the present invention providesnovel compounds, wherein:

X is C₁₋₄ alkylene selected from methylene, ethylene, propylene, andbutylene; wherein C₁₋₄ alkylene is substituted with 0-2 R⁷;

R⁷, at each occurrence, is selected from C₁₋₃ alkyl, (CH₂)_(r)OH,(CH₂)_(r)OR^(7d), (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)-phenylsubstituted with 0-3 R^(7e);

R^(7d), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, (CH₂)_(r)NR^(7f)R^(7f);

R^(7f) is selected from H and C₁₋₆ alkyl; and

Y is selected from NHC(═O)NH, NHC(═NR^(a))NH, NHC(═CHCN)NH, C(O)NH, andNHC(O).

In certain embodiments, the present invention provides novel compoundsof formula I-ii:

wherein:

R⁸, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(8a)R^(8a)′, NO₂, CN, OH,(CH₂)_(r)OR^(8d), (CH₂)_(r)C(O)R^(8b), (CH₂)_(r)C(O)NR^(8a)R^(8a)′,(CH₂)_(r)NR^(8f)C(O)R^(8b), (CH₂)_(r)S(O)_(p)R^(8b),(CH₂)_(r)S(O)₂NR^(8a)R^(8a)′, (CH₂)_(r)NR^(8f)S(O)₂R^(8b), and(CH₂)_(r)phenyl substituted with 0-3 R^(8e);

R^(8a) and R^(8a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(8e);

R^(8b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(8e);

R^(8d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(8e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(8f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

R¹⁰, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(10a)R^(10a)′, NO₂, CN, OH,(CH₂)_(r)OR^(10d), (CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10a)R^(10a)′,R^(10f)C(O)R^(10b), (CH₂)_(r)S(O)_(p)R^(10b),(CH₂)_(r)S(O)₂NR^(10a)R^(10a)′, (CH₂)_(r)NR^(10f)S(O)₂R^(10b), and(CH₂)_(r)phenyl substituted with 0-3 R^(10e);

R^(10a) and R^(10a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(10e);

R^(10b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(10e);

R^(10d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(10e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(10f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

In certain embodiments of formula I-ii, the present invention providesnovel compounds, wherein:

R⁵ is CH₂phenyl substituted with 0-3 R¹⁰;

K is selected from CH₂ and CHR⁵;

L is selected from CH₂ and CHR⁵;

R⁹, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(9a)R^(9a)′, NO₂, CN, OH,(CH₂)_(r)OR^(9d), (CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9a)R^(9a)′,(CH₂)_(r)NR^(9f)C(O)R^(9b), (CH₂)_(r)S(O)_(p)R^(9b),(CH₂)_(r)S(O)₂NR^(9a)R^(9a)′, (CH₂)_(r)NR^(9f)S(O)₂R^(9b),(CH₂)_(r)phenyl substituted with 0-3 R^(9e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(9e);

R^(9a) and R^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e);

R^(9b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e);

R^(9d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(9f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

In certain embodiments of formula I-ii, the present invention providesnovel compounds, wherein:

X is C₁₋₄ alkylene selected from methylene, ethylene, propylene, andbutylene; wherein C₁₋₄ alkylene is substituted with 0-2 R⁷;

R⁷, at each occurrence, is selected from C₁₋₃ alkyl, (CH₂)_(r)OH,(CH₂)_(r)OR^(7d), (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)-phenylsubstituted with 0-3 R^(7e);

R^(7d), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, (CH₂)_(r)NR^(7f)R^(7f);

R^(7f) is selected from H and C₁₋₆ alkyl; and

Y is selected from NHC(═O)NH, NHC(═NR^(a))NH, NHC(═CHCN)NH, C(O)NH, andNHC(O).

In certain embodiments, the present invention provides novel compoundsof formula I, wherein:

when v is 0, L is CH₂;

when v is 1, M is CH₂; or

when v is 2, the M adjacent to the carbon bearing R³ is CH₂.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein:

A is selected from phenyl, cyclohexyl, cyclopentyl, and cyclopropyl;

R⁷, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, F, Cl, Br, I, (CH₂)_(r)OH, (CH₂)_(r)OR^(7d),(CH₂)_(r)NR^(7a)R^(7a)′, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)-phenylsubstituted with 0-3 R^(7e);

R^(7a) and R^(7a)′, at each occurrence, are selected from H, C₁₋₆ alkyl;

R^(7d), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;

R^(7e) is selected from H and C₁₋₆ alkyl;

R⁷′ is H;

R⁸, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(8a)R^(8a)′, NO₂, CN, OH,(CH₂)_(r)OR^(8d), (CH₂)_(r)C(O)R^(8b), (CH₂)_(r)C(O)NR^(8a)R^(8a)′,(CH₂)_(r)NR^(8f)C(O)R^(8b), (CH₂)_(r)S(O)_(p)R^(8b),(CH₂)_(r)S(O)₂NR^(8a)R^(8a)′, (CH₂)_(r)NR^(8f)S(O)₂R^(8b), and(CH₂)_(r)phenyl substituted with 0-3 R^(8e);

R^(8a) and R^(8a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(8e);

R^(8b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(8e);

R^(8d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(8e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(8f), at each occurrence, is selected from H and C₁₋₅ alkyl; and

R¹¹, at each occurrence, is selected from H, and C₁₋₈ alkyl.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein:

R¹ is selected from a carbocyclic residue substituted with 0-3 R⁹,wherein the carbocyclic residue is selected from phenyl and C₃₋₆cycloalkyl; and a heterocyclic system substituted with 0-3 R⁹, whereinthe heterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein:

R⁵ is selected from (CR⁵′H)_(t)-phenyl substituted with 0-3 R¹⁰; and a(CR⁵′H)_(t)-heterocyclic system substituted with 0-3 R¹⁰, wherein theheterocyclic system is selected from pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein v is 1, M is CH₂, and J is CH₂.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein R³ is H and R⁴ is absent.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein:

R⁹, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(9a)R^(9a)′, NO₂, CN, OH,(CH₂)_(r)OR^(9d), (CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9a)R^(9a)′,(CH₂)_(r)NR^(9f)C(O)R^(9b), (CH₂)_(r)S(O)_(p)R^(9b),(CH₂)_(r)S(O)₂NR^(9a)R^(9a)′, (CH₂)_(r)NR^(9f)S(O)₂R^(9b),(CH₂)_(r)phenyl substituted with 0-3 R^(9e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(9e);

R^(9a) and R^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e);

R^(9b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(9e);

R^(9d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(9f), at each occurrence, is selected from H, and C₁₋₅ alkyl;

R¹⁰, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(10a)R^(10a)′, NO₂, CN, OH,(CH₂)_(r)OR^(10d), (CH₂)_(r)C(O)R^(10b), (CH₂)_(r)C(O)NR^(10a)R^(10a)′,(CH₂)_(r)NR^(10f)C(O)R^(10b), (CH₂)_(r)S(O)_(p)R^(10b),(CH₂)_(r)S(O)₂NR^(10a)R^(10a)′, (CH₂)_(r)NR^(10f)S(O)₂R^(10b), and(CH₂)_(r)phenyl substituted with 0-3 R^(10e);

R^(10a) and R^(10a)′, at each occurrence, are selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(10e);

R^(10b), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(10e);

R^(10d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(10e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(10f), at each occurrence, is selected from H, and C₁₋₅ alkyl.

In certain preferred embodiments, the present invention provides novelcompounds of formula I, wherein K is CH₂, L is CHR⁵, wherein R⁵ issubstituted with 0-3 R¹⁰.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein R⁵ is a benzyl group (CH₂-phenyl) substituted with0-3 R¹⁰.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein R¹ is phenyl substituted with 0-3 R⁹.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein X is propylene substituted with 0-3 R⁷.

In a certain embodiments, the present invention provides novel compoundsof formula I, wherein:

R⁷, at each occurrence, is selected from C₁₋₃ alkyl, (CH₂)_(r)OH,(CH₂)_(r)OR^(7d), (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)-phenylsubstituted with 0-3 R^(7e);

R^(7d), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, (CH₂)_(r)NR^(7f)R^(7f);and

R^(7f) is selected from H and C₁₋₆ alkyl.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein:

R², at each occurrence, is selected from H, C₁₋₈ alkyl,(CR²′R²″)_(q)NR^(12a)R^(12a)′, (CR²′R²″)_(w)OH,(CR²′R²″)_(w)O(CR²′R²″)_(r)R^(12d),(CR²′R²″)_(r)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)NR^(12a)C(NR^(a))NR^(12a)R^(12a)′,(CR²′R²″)_(r)C(O)NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)S(O)₂NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)S(O)₂(CR²′R²″)_(r)R^(12b), C₁₋₆ haloalkyl, C₂₋₈alkenyl substituted with 0-3 R^(12c), C₂₋₈ alkynyl substituted with 0-3R^(12c), a (CR²′R²″)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(12c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(12c);

alternatively, R² is an amino acid residue; and

R²′ and R²″, at each occurrence, are selected from H, C₁₋₈ alkyl, C₂₋₈alkenyl, (CH₂)_(r)OH, (CH₂)_(r)OR^(2b), (CH₂)_(r)C(O)R^(2b),(CH₂)_(r)C(O)NR^(2a)R^(2a)′, (CH₂)_(r)NR^(2d)C(O)R^(2a).

In certain embodiments, the present invention provides novel compoundsof formula I, wherein:

R², at each occurrence, is selected from H, C₁₋₈ alkyl,(CH₂)_(q)NR^(12a)R^(12a)′, (CH₂)_(w)OH, (CH)_(w)O(CR²′R²″)_(r)R^(12d),(CR²′R²″)_(r)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)NR^(12a)C(NR^(a))NR^(12a)R^(12a)′,(CR²′R²″)_(r)C(O)NR^(12a)R^(12a)′, (CR²′R²″)_(q)NR^(12f)C(O)(CR²′R²″)_(r)R^(12b), (CR²′R²″)_(w)S(O)₂NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR_(12f)S(O)₂(CR²′R²″)_(r)R^(12b);

R²′ and R²″ are H;

r is selected from 0, 1, and 2; and

w and q are selected from 2 and 3.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein X is unsubstituted propylene.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein R⁵ is substituted with 0-2 R¹⁰.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein:

R¹⁰, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, C(O)C₁₋₄ alkyl,(CH₂)_(r)NR^(10a)R^(10a)″, CN, OH, OCF₃, (CH₂)_(r)OR^(10d);

R^(10a) and R^(10a)′, at each occurrence, are selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; and

R^(10d) is C₁₋₆ alkyl.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein R¹⁰ is selected from F, Cl, Br, OCF₃, and CF₃.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein R¹ is substituted with 0-2 R⁹.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein:

R⁹, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, F, NO₂, CN, (CHR′)_(r)NR^(9a)R^(9a)′, (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(9d), (CHR′)_(r)C(O)(CHR′)_(r)R^(9b),(CHR′)_(r)C(O)NR^(9a)R^(9a)′, (CHR′)_(r)NR^(9f)C(O)(CHR′)_(r)R^(9b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(9d), (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(9b),(CHR′)_(r)S(O)₂NR^(9a)R^(9a)′, (CHR′)_(r)NR^(9f)S(O)₂(CHR′)_(r)R^(9b),CF₃, OCF₃, (CHR′)_(r)phenyl substituted with 0-3 R^(9e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(9e);

R^(9a) and R^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(9e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(9e);

R^(9b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(9e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(9e);

R^(9d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₁₋₆ alkyl substituted with 0-3 R^(9e), a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(9e), and a (CH₂)_(r)5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(9e);

R^(9e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl; and

R^(9f), at each occurrence, is selected from H, C₁₋₅ alkyl, C₃₋₆cycloalkyl, and phenyl.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein R¹ is phenyl substituted with R⁹ groups whichoccupy the 3, or the 5, or both the 3 and 5 positions on the phenylring.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein R⁹, at each occurrence, is selected fromC(O)R^(9b), C(O)OR^(d), C(O)OH, CN, and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(9e).

In certain embodiments, the present invention provides novel compoundsof formula I, wherein Y is selected from NR¹¹C(═S) NR¹¹, NR¹¹C(═NR^(a))NR¹¹, NR¹¹C(═CHCN)NR¹¹, NR¹¹C(═CHNO₂)NR¹¹, NR¹¹C(═C(CN)₂)NR¹¹, NR¹¹,C(O), S(O)₂NR¹¹, NR¹¹S(O)₂, NR¹¹S(O)₂NR¹¹, C(O)NR¹¹, NR¹¹C(O),NR¹¹C(O)O, OC(O)NR¹¹, and S(O)_(p).

In certain embodiments, the present invention provides novel compoundsof formula I, wherein Y is selected from NR¹¹C(═NR^(a))NR¹¹,NR¹¹C(═CHCN)NR¹¹, NR¹C(═CHNO₂)NR¹¹, and NR¹¹C(═C(CN)₂)NR¹¹.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein Y is NR¹¹C(═NCN)NR¹¹.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein Y is NR¹¹C(═C(CN)₂)NR¹¹.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein Y is selected from NR¹¹C(═C(CN)₂)NR¹¹ andNR¹¹C(═NCN)NR¹¹, and R¹¹, at each occurrence, is selected from H andC₁₋₆ alkyl.

In certain embodiments, the present invention provides novel compoundsof formula I, wherein R⁹, at each occurrence, is selected fromC(O)R^(9b), C(O)OR^(d), C(O)OH, CN, and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(9e).

In certain embodiments, the present invention provides novel compoundsof formula I, wherein:

X is (CR⁷R⁷)_(t)—A—(CR⁷R⁷)_(t) substituted with 0-3 R⁸;

R⁷, at each occurrence, is selected from C₁₋₃ alkyl, (CH₂)_(r)OH,(CH₂)_(r)OR^(7d), (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)-phenylsubstituted with 0-3 R^(7e);

R^(7d), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl;

R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, (CH₂)_(r)NR^(7f)R^(7f);

R^(7f) is selected from H and C₁₋₆ alkyl;

R⁸, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(8f)R^(8f), NO₂, CN, OH,(CH₂)_(r)OR^(8d), and (CH₂)_(r)phenyl substituted with 0-3 R^(8e);

R^(8d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;

R^(8e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and

R^(8f), at each occurrence, is selected from H and C₁₋₅ alkyl.

In certain preferred embodiments, the present invention provides novelcompounds of formula I, wherein the compound of formula I is selectedfrom:

(+)-trans-N-(3-cyanophenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-cyanophenyl)-N′-[3-[4-(4-phenylmethyl)-1-methyl-2-piperidinyl]propylurea,

(±)-trans-N-(3-cyanophenyl)-N′-[3-[4-(4-phenylmethyl)-1-acetyl-2-piperidinyl]propylurea,

(±)-trans-N-phenyl-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,

(±)-trans-N-(3-cyanophenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-carbomethoxyphenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-carboethoxyphenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-fluorophenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(4-fluorophenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-chlorophenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(4-chlorophenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-methoxyphenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-phenyl-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-cyano-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-acetyl-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-carbomethoxy-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-carboethoxy-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-fluoro-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(4-fluoro-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-chloro-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(4-chloro-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-methoxy-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-phenyl-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,

(±)-trans-N-(3-cyanophenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-carbomethoxyphenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-carboethoxyphenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-fluorophenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(4-fluorophenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-chlorophenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(4-chlorophenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-methoxyphenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-phenyl-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-cyano-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-acetyl-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-carbomethoxy-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-carboethoxy-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-fluoro-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(4-fluoro-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-chloro-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(4-chloro-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-methoxy-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-phenyl-N′-[4-(phenylmethyl)-2-piperidinyl]methyl urea,

(±)-trans-N-(3-cyanophenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-carbomethoxyphenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-carboethoxyphenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-fluorophenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(4-fluorophenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-chlorophenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(4-chlorophenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-methoxyphenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-phenyl-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-cyano-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-acetyl-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-carbomethoxy-phenyl)-N′-[4-(4-fluorophenylmnethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-carboethoxy-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-fluoro-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl)methylurea,

(±)-trans-N-(4-fluoro-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-chloro-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(4-chloro-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-methoxy-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-phenyl-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propyl urea,

(±)-cis-N-(3-cyanophenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-acetylphenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-carbomethoxyphenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-carboethoxyphenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-fluorophenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(4-fluorophenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-chlorophenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(4-chlorophenyl)-N′-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-methoxyphenyl)-N-[3-[4-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-phenyl-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-cyano-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-acetyl-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-carbomethoxy-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-carboethoxy-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-fluoro-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(4-fluoro-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-chloro-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(4-chloro-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-methoxy-phenyl)-N′-[3-[4-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-phenyl-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethyl urea,

(±)-cis-N-(3-cyanophenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-acetylphenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-carbomethoxyphenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-carboethoxyphenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-fluorophenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(4-fluorophenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-chlorophenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(4-chlorophenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-methoxyphenyl)-N′-[2-[4-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-phenyl-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-cyano-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-acetyl-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-carbomethoxy-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-carboethoxy-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-fluoro-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(4-fluoro-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-chloro-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(4-chloro-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-methoxy-phenyl)-N′-[2-[4-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-phenyl-N′-[4-(phenylmethyl)-2-piperidinyl]methyl urea,

(±)-cis-N-(3-cyanophenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-acetylphenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-carbomethoxyphenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-carboethoxyphenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-fluorophenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(4-fluorophenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-chlorophenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(4-chlorophenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-methoxyphenyl)-N′-[4-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-phenyl-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,

(±)-cis-N-(3-cyano-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-acetyl-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-carbomethoxy-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-carboethoxy-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-fluoro-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(4-fluoro-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-chloro-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(4-chloro-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-methoxy-phenyl)-N′-[4-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-phenyl-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,

(±)-trans-N-(3-cyanophenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-carbomethoxyphenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-carboethoxyphenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-fluorophenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(4-fluorophenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-chlorophenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(4-chlorophenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-methoxyphenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-phenyl-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-cyano-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-acetyl-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-carbomethoxy-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-carboethoxy-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-fluoro-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(4-fluoro-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-chloro-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(4-chloro-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-methoxy-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-trans-N-phenyl-N′-([2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,

(±)-trans-N-(3-cyanophenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-carbomethoxyphenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-carboethoxyphenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-fluorophenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(4-fluorophenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-chlorophenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(4-chlorophenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-methoxyphenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-phenyl-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-cyano-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-acetyl-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-carbomethoxy-phenyl)-N′-[2-(5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-carboethoxy-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-fluoro-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(4-fluoro-phenyl)-N′-[2-5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-chloro-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(4-chloro-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-(3-methoxy-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-trans-N-phenyl-N′-[5-(phenylmethyl)-2-piperidinyl]methyl

(±)-trans-N-(3-cyanophenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-carbomethoxyphenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-carboethoxyphenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-fluorophenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(4-fluorophenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-chlorophenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(4-chlorophenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-methoxyphenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-phenyl-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-cyano-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-acetyl-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-carbomethoxy-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-carboethoxy-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-fluoro-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(4-fluoro-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-chloro-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(4-chloro-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-trans-N-(3-methoxy-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-phenyl-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propyl urea,

(±)-cis-N-(3-cyanophenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-acetylphenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-carbomethoxyphenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-carboethoxyphenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-fluorophenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(4-fluorophenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-chlorophenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(4-chlorophenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-methoxyphenyl)-N′-[3-[5-(phenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-phenyl-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-cyano-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-acetyl-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-carbomethoxy-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-carboethoxy-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-fluoro-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(4-fluoro-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-chloro-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(4-chloro-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-methoxy-phenyl)-N′-[3-[5-(4-fluorophenylmethyl)-2-piperidinyl]propylurea,

(±)-cis-N-phenyl-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethyl urea,

(±)-cis-N-(3-cyanophenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-acetylphenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-carbomethoxyphenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-carboethoxyphenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-fluorophenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(4-fluorophenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-chlorophenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(4-chlorophenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-methoxyphenyl)-N′-[2-[5-(phenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-phenyl-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-cyano-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-acetyl-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-carbomethoxy-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-carboethoxy-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-fluoro-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(4-fluoro-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-chloro-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(4-chloro-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-(3-methoxy-phenyl)-N′-[2-[5-(4-fluorophenylmethyl)-2-piperidinyl]ethylurea,

(±)-cis-N-phenyl-N′-[5-(phenylmethyl)-2-piperidinyl]methyl urea,

(±)-cis-N-(3-cyanophenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-acetylphenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-carbomethoxyphenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-carboethoxyphenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-fluorophenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(4-fluorophenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-chlorophenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(4-chlorophenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-methoxyphenyl)-N′-[5-(phenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-phenyl-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,

(±)-cis-N-(3-cyano-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-acetyl-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-carbomethoxy-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-carboethoxy-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methyl urea,

(±)-cis-N-(3-fluoro-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(4-fluoro-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(3-chloro-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea,

(±)-cis-N-(4-chloro-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea, and

(±)-cis-N-(3-methoxy-phenyl)-N′-[5-(4-fluorophenylmethyl)-2-piperidinyl]methylurea.

In other preferred embodiments, the present invention provides novelcompounds of formula I, wherein the compound of formula I is selectedfrom:

(±)-cis-N-{3-[4-benzyl-2-piperidinyl]propyl}-N′-(3-cyanophenyl)urea,

(±)-trans-N-(3-cyanophenyl)-N′-[2-[4-(benzyl)-2-piperidinyl]ethyl urea,

(±)-trans-N{3-[4-benzyl-2-piperidinyl]propyl}-3-cyanobenzamide,

(±)-trans-N-(3-acetylphenyl)-N′-[2-[4-(benzyl)-2-piperidinyl]ethyl urea,

(±)-trans-N{3-[4-benzyl-2-piperidinyl]propyl}-4-fluorobenzenesulfonamide,

(±)-trans-N{3-[4-benzyl-2-piperidinyl]propyl}benzamide,

(±)-cis-N-(3-cyanophenyl)-N′-[3-[4-(4-fluorobenzyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(4-fluorobenzyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-acetylphenyl)-N′-[3-[4-(4-fluorobenzyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-chlorophenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propylurea,

(±)-trans-N-(phenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propyl urea,

(±)-trans-N-(3-fluorophenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-methoxyphenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propylurea,

(±)-trans-N-(4-carboethoxyhenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propylurea,

(±)-trans-N-(4-fluorophenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-trifluoromethylphenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propylurea,

(±)-cis-N-(3-cyanophenyl)-N′-[3-[4-(benzyl)-1-propyl-2-piperidinyl]propylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(benzyl)-1-propyl-2-piperidinyl]propylurea,

(±)-cis-N-(3-acetylphenyl)-N′-[3-[4-(4-fluorobenzyl)-1-propyl-2-piperidinyl]propylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(4-fluorobenzyl)-1-propyl-2-piperidinyl]propylurea,

(±)-trans-N-(3-cyanophenyl)-N′-[4-[4-(benzyl)-2-piperidinyl]butyl urea,

(±)-trans-N-(3-acetylphenyl)-N′-[4-[4-(benzyl)-2-piperidinyl]butyl urea,

N-(3-acetylphenyl)-N′-{[3-[2S,4S]-4-(4-fluorobenzyl)piperidinyl]propyl}urea,

N-(3-acetylphenyl)-N′-{[4-[2R,4R]-4-(4-fluorobenzyl)-2-piperidinyl]butyl}urea,

N-(3-cyanophenyl)-N′-{[4-[2R,4R]-4-(4-fluorobenzyl)piperidinyl]butyl}urea,

N-(3-acetylphenyl)-N′-{3-[(2S,4R)-4-(2,4-difluorobenzyl)piperidinyl]propyl}urea,

N-{3-[(2S,4R)-1-allyl-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3,5-diacetylphenyl)urea,

N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-hydroxyethyl)piperidinyl]propyl}urea,

N-{3-[(2S,4R)-1-acetyl-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3,5-diacetylphenyl)urea,

N-(3,5-diacetylphenyl)-N′-{3-[(2S)-4-(4-fluorobenzyl)-1-(2-fluoroethyl)piperidinyl]propyl}urea,

(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(benzyl)-1-(2-hydroxyethyl)-2-piperidinyl]propylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(benzyl)-1-methyl-2-piperidinyl]propylurea,

(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(benzyl)-1-ethyl-2-piperidinyl]propylurea,

N-(3-acetylphenyl)-N′-{-[3-(2R,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,

N-(3-acetylphenyl)-N′-{-[3-(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,

N-(3-acetylphenyl)-N′-{-[3-(2S,4R)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}urea,

N-(3-acetylphenyl)-N′-{-[3-(2S,4R)-4-(4-fluorobenzyl)-1-methylpiperidinyl]propyl}urea,

N-(3-acetylphenyl)-N′-{-[3-(2S,4R)-4-(4-fluorobenzyl)-1-(2-hydroxyethyl)piperidinyl]propyl}urea,

[(2S,4R)-2-(3-{-[(3-acetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)piperidinyl]aceticacid,

N-(3-acetylphenyl)-N′-{3-[(2S,4R)-1-benzyl-4-(4-fluorobenzyl)piperidinyl]propyl}urea,

(±)-trans-N-{3-[(4-benzyl-2-piperidinyl]propyl}-N′-(3-fluoro-4-methylphenyl)urea,

(±)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-N′-(3,4-dimethoxyphenyl)urea,

(±)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-N′-(6-methoxy-3-pyridinyl)urea,

(±)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-N′-(1H-indazol-6-yl)urea,

N-(3-acetylphenyl)-N′-{3-[(2S,4R)-1-(cyclopropylmethyl)-4-(4-fluorobenzyl)piperidinyl]propyl)urea,

N-(3-cyanophenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,

N-(3-cyanophenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}urea,

N-(3-acetylphenyl)-N′-(3-[(2S,4R)-1-allyl-4-(4-fluorobenzyl)piperidinyl]propyl}urea,

N-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea,

N-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}-N′-(3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea,

(2S,4R)-2-(3-{[(E)-{[(E)-amino(oxo)methyl]imino}(3,5-diacetylanilino)methyl]amino}propyl)-4-(4-fluorobenzyl)-N-methyl-1-piperidinecarboxamide,

N-[(E)-({3-[(2S,4R)-1-acetyl-4-(4-fluorobenzyl)piperidinyl]propyl}amino)(3,5-diacetylanilino)methylidene]urea,

N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-hydroxyethyl)piperidinyl]propyl}guanidine,

N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,

N-(3,5-diacetylphenyl)-N′-{3-[(2S)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}urea,

N-[(E)-(3,5-diacetylanilino)({3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}amino)methylidene]urea,

N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}guanidine,

(2S,4R)-2-(3-{[(3,5-diacetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)-1-piperidinecarboximidamide,

N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}guanidine,

(2S,4S)-2-(3-{[(3-acetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)-1-piperidinecarboximidamide,

N-{3-[(2S,4R)-1-(aminoacetyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3,5-diacetylphenyl)urea,

N-{3-[(2S,4R)-1-allyl-4-(4-fluorobenzyl)piperidinyl]propyl}-N″-cyano-N′-(3,5-diacetylphenyl)guanidine,

N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-fluoroethyl)piperidinyl]propyl}guanidine,

N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-propynyl)piperidinyl]propyl}guanidine,

N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-methylpiperidinyl]propyl}guanidine,

N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-1-ethyl-4-(4-fluorobenzyl)piperidinyl]propyl}guanidine,

N-[3,5-bis(1-methyl-1H-tetraazol-5-yl)phenyl]-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,

N-{3-[(2S,4R)-1-acetyl-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-[3,5-bis(1-methyl-1H-tetraazol-5-yl)phenyl]urea,

N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-1-(2,2-difluoroethyl)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,

N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(methylsulfonyl)piperidinyl]propyl}urea,

N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propionylpiperidinyl]propyl}urea,

N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-isobutyrylpiperidinyl]propyl}urea,

(2S,4R)-2-(3-{[(3,5-diacetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)-N-methyl-1-piperidinecarboxamide,

(2S,4R)-2-(3-{[(3,5-diacetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)-1-piperidinecarboxamide,

N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-pyridinylmethyl)piperidinyl]propyl}urea,

2-[(2S,4R)-2-(3-{-[(3,5-diacetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)piperidinyl]acetamide,

N-{3-[(2S,4R)-1-[(2S)-2-aminopropanoyl]-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3,5-diacetylphenyl)urea,

N-{3-[(2S,4R)-1-[(2R)-2-aminopropanoyl]-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3,5-diacetylphenyl)urea,

N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-propynyl)piperidinyl]propyl}urea,

1-(3-{[(E)-1-({3-[(2S)-4-(4-fluorobenzyl)piperidinyl]propyl}amino)-2-nitroethenyl]amino}phenyl)ethanone,

(±)-trans-N-{3-[4-(benzyl)-2-piperidinyl]propyl}-N′-[3-(phenylsulfonyl)phenyl]urea,

(±)-trans-N-{3-[4-(benzyl)-2-piperidinyl]propyl}-N′-[3-chloro-4-(diethylamino)phenyl]urea,

(±)-trans-N-(3-{[({3-[4-benzyl-2-piperidinyl)propyl}amino)carbonyl]amino}phenyl)acetamide,

(±)-trans-N-{3-[4-benzylpiperidinyl]-2-propyl}-N′-[3-(1-hydroxyethyl)phenyl]urea,

(±)-trans-dimethyl5-{[({3-[4-benzyl-2-piperidinyl]propyl}amino)carbonyl]amino}isophthalate,

(±)-trans-ethyl3-{-[({3-[4-benzyl-2-piperidinyl]propyl}amino)carbonyl]amino}benzoate,

(±)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-N′-(3-chlorophenyl)urea,

N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-oxo-propyl)piperidinyl]propyl}urea,

N-[3-(2-{3-[(3,5-diacetylanilinocarbonyl)amino}propyl}-4-(4-fluorobenzyl)-1-piperidinyl)propyl]acetamide,

N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(3-hydroxypropyl)piperidinyl]propyl}urea,

N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-oxo-propyl)piperidinyl]propyl}guanidine,and

N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(3-hydroxypropyl)piperidinyl]propyl}guanidine.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of the present invention.

In another embodiment, the present invention provides a method formodulation of chemokine receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention.

In another embodiment, the present invention provides a method fortreating inflammatory disorders comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of thepresent invention

In another embodiment, the present invention provides a method fortreating or preventing disorders selected from asthma, allergicrhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathicpulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections,allergic colitis, eczema, conjunctivitis, transplantation, familialeosinophilia, eosinophilic cellulitis, eosinophilic pneumonias,eosinophilic fasciitis, eosinophilic gastroenteritis, drug inducedeosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome,lymphoma, Hodgkin's disease, and colonic carcinoma.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

When any variable (e.g., R^(a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(a), then saidgroup may optionally be substituted with up to two R^(a) groups andR^(a) at each occurrence is selected independently from the definitionof R^(a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₈ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl; “Alkenyl” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain, such as ethenyl, propenyl, and the like.“Alkynyl” is intended to include hydrocarbon chains of either a straightor branched configuration and one or more unsaturated triplecarbon-carbon bonds which may occur in any stable point along the chain,such as ethynyl, propynyl, and the like. “C₃₋₆ cycloalkyl” is intendedto include saturated ring groups having the specified number of carbonatoms in the ring, including mono-, bi-, or poly-cyclic ring systems,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl in the case of C₇ cycloalkyl.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

The compounds of Formula I can also be quaternized by standardtechniques such as alkylation of the piperidine or pyrrolidine with analkyl halide to yield quaternary piperidinium salt products of FormulaI. Such quaternary piperidinium salts would include a counterion. Asused herein, “counterion” is used to represent a small, negativelycharged species such as chloride, bromide, hydroxide, acetate, sulfate,and the like.

As used herein, the term “piperidinium spirocycle or pyrrolidiniumspirocycle” is intented to mean a stable spirocycle ring system, inwhich the two rings form a quarternary nitrogene at the ring junction.

As used herein, the term “5-6-membered cyclic ketal” is intended to mean2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane andtheir derivatives.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3- to 10-membered monocyclic or bicyclic or 7- to13-membered bicyclic or tricyclic, any of which may be saturated,partially unsaturated, or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated, partiallyunsaturated, or unsaturated (aromatic), and which consists of carbonatoms and from 1 to 4 heteroatoms independently selected from the groupconsisting of N, O and S and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Thenitrogen and sulfur heteroatoms may optionally be oxidized. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. If specifically noted, anitrogen in the heterocycle may optionally be quaternized. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. Asused herein, the term “aromatic heterocyclic system” is intended to meana stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-memberedbicyclic heterocyclic aromatic ring which consists of carbon atoms andfrom 1 to 4 heterotams independently selected from the group consistingof N, O and S.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocyclesinclude, but are not limited to, pyridinyl, thiophenyl, furanyl,indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl,benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,imidazolyl, indolyl, isoidolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “amino acid” or “amino acid residue” isintended to have its art-recognized meaning as a molecule containingboth an amino group and a carboxyl group separated by a carbon.Embodiments of amino acids include α-amino acids; i.e., carboxylic acidsof general formula HOOC-CH(NH2)—(side chain). Side chains of amino acidsinclude naturally occurring and non-naturally occurring moieties.Non-naturally occurring (i.e., unnatural) amino acid side chains aremoieties that are used in place of naturally occurring amino acid sidechains in, for example, amino acid analogs. See, for example, Lehninger,Biochemistry, Second Edition, Worth Publishers, Inc, 1975, pages 73-75,the disclosure of which is hereby incorporated by reference. In certainembodiments, substituent groups for the compounds include the residue ofan amino acid after removal of the hydroxyl moiety of the carboxyl groupthereof; i.e., groups of Formula —C(═O) CH(side chain) (N(G)₂)—, whereinG is a group including, but not limited to, hydrogen, a nitrogenprotecting group, or another amino acid.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

“Prodrugs” are intended to include any covalently bonded carriers whichrelease the active parent drug according to formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of formula (I) are prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Prodrugs include compounds of formula (I) wherein a hydroxy,amino, or sulfhydryl group is bonded to any group that, when the prodrugor compound of formula (I) is administered to a mammalian subject,cleaves to form a free hydroxyl, free amino, or free sulfhydryl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of formula (I), and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

SYNTHESIS

The following abbreviations are used herein: “THF” as used herein isintended to mean tetrahydrofuran, “EtOAc” as used herein is intended tomean ethyl acetate, “DMAP” as used herein is intended to mean4-N,N-dimethylamino pyridine, “9-BBN” as used herein is intended to mean9-borabicyclo [3.3.1]nonane, “Boc₂O” as used herein is intended to meanDi-tert-Butyl dicarbonate, “NMO” as used herein intended to meanN-methyl morpholine-N-oxide, “TPAP” as used herein is intended to meantetrapropylammonium perruthenate, “TFA” as used herein is intended tomean trifluoroacetic acid. The compounds of Formula I can be preparedusing the reactions and techniques described below.

The reactions are performed in a solvent appropriate to the reagents andmaterials employed and suitable for the transformations being effected.It will be understood by those skilled in the art of organic synthesisthat the functionality present on the molecule should be consistent withthe transformations proposed. This will sometimes require a judgment tomodify the order of the synthetic steps or to select one particularprocess scheme over another in order to obtain a desired compound of theinvention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene and Wuts (Protective Groups In Organic Synthesis,Wiley and Sons, 1991).

Compounds of the Formula Ia-d are prepared by alkylating heterocyclesIIa-d by using the appropriate conditions according to Scheme 1. Thus,heterocycles Ia-d can be alkylated with an alkyl sulfonate or alkylhalide according to the general methods described for thistransformation in March, J. “Advanced Organic Chemistry,” 4th Ed., JohnWiley and Sons, New York, 1992, pp. 411-413 (Herein after March, 4th Ed)Heterocycles IIa-d can also be treated with an aldehyde and anappropriate reducing agent to give Ia-d as described in March, 4th Ed.(pp. 898-900.)

The required aldehydes can be prepared by methods generally known tothose skilled in the art of organic synthesis. Furthermore, heterocyclesIIa-d can be acylated and the resulting amides reduced by theappropriate reducing agent to give Ia-d using procedures described inMarch, 4th Ed. (pp. 419-421 and 1212-1213, respectively.) HeterocycleIIa can be prepared by the following sequence outlined in Scheme 2.Imide III can be alkylated with an alkyl sulfonate, triflate or halideaccording to the methods described in the literature, more specifically,but not limited to, as described by Dieter, R. K. et al., Journal ofOrganic Chemistry, 1996, Vol. 61, pp. 4180-4184 to give IV. Substitutedimide IV can then be reduced to the α-alkoxy or α-hydroxy urethane Vaccording to the methods described in the literature, more specifically,but not limited to, as described by Nagasaka, T. et. al, Heterocycles,Vol. 24, No. 5, 1986.

Ionization of urethane V with a Bronstead or Lewis Acid generates anelectrophilic acyl iminium ion which can be treated with a variety ofnucleophiles according to the general methods outlined by, but notlimited to, Shono, T. Tetrahedron, Vol. 40. No. 5, pp. 811-850, 1984.,to give heterocycle VI. The side chain functionality (X) of VI can thenbe further modified or functionalized, if necessary, and the nitrogendeprotected (removal of Q), both using methods known to those skilled inthe art of organic synthesis to provide heterocycle IIa.

By way of further illustration (Scheme 2a), when X═—CH₂CH═CH₂ (allyl),manipulation by hydroboration, conversion to an alkyl or aryl sulfonate,displacement with azide and hydrogenation provides amine XXX. Reactionwith the appropriate acylating reagent and removal of Q will provideheterocycles of the formula IIa. All of these simple transformations areknown to those skilled in the art of organic synthesis. Furthermore, thepreparation and use of several of the acylating reagents described inScheme 2a is illustrated in P. Traxler, et al., J. Med. Chem. (1997),40, 3601-3616 for reagent 1b and 1d; see K. S. Atwal, J. Med. Chem.(1998) 41, 271 for reagent 1c; and see also J. M. Hoffman, et al., J.Med. Chem. (1983) 26, 140-144).

Heterocycle IIb can be prepared by the sequence outlined in Scheme 3.Unsaturated imide VIII can be prepared by the methods described in theliterature, more specifically, but not limited to, as described byComins, D., et al., Adv. Nitrogen Heterocycl., 1996, Vol. 2, pp.251-294. Thus, pyridines of the formula VII can be converted to theirpyridinium salts at low temperature, treated with an appropriatenucleophile and subsequently hydrolized to vinylogous imides of theformula VIII. This procedure can be conveniently performed to produceracemic material or be slightly modified to produce material of highenantiomeric excess. At this juncture, the urethane functionality (Q)can be modified, if warranted, to facilitate more convenient removal ofQ at the end of the synthetic sequence. Imide VIII can be reducedaccording to methods known to those skilled in the art of organicsynthesis to give ketone IX. Ketone IX can be converted to urethane Xaccording to methods described in March, 4th Ed., pp. 956-963. Theresulting urethane X can be processed in two separate manners. The sidechain X can be manipulated prior to reduction of the olefin to give XI.Olefin XI and/or urethane X can then be reduced with reagents known tothose skilled in the art of organic synthesis.

For example, by treatment with H₂(g) accompanied by the appropriatecatalyst (including, but not limited, to PtO₂ or Pd on carbon) or bytreatment with an alkaline earth metal such as lithium, sodium orcalcium in the appropriate solvent mixture (ammonia mixed with THF ordiethyl ether) to give XII or XIII, respectively. Heterocycle IIb can beprepared from XIII and/or XII with similar transformations describedabove for heterocycle VI.

Imides similar to VIII (XIV) can also be converted into heterocycles ofthe formula IIc according to Scheme 4. Thus, treatment of XIV withstrong base followed by alkylation of the resulting enolate with anappropriate electrophile generates unsaturated imide XV. Reaction of XVwith an organometallic derivative according to, but not limited to,procedures described in March, 4th Ed., pp. 797-803 would provide ketoneXVI. Reduction of ketone XVI using a variety of conditions described in,but not limited to, March, 4th Ed., pp. 1209-1211 would provide urethaneXVII. Manipulation of XVII as previously described for VI and XII willyield heterocyles of the formula IIc.

Imide VIII can also be used in the formation of compounds of the formulaIId (Scheme 5). Thus, reaction of VIII with an organometallic reagent inan analogous fashion to the formation of XVI would provide XVIII.Reduction of the ketone XVIII using conditions described for ketone XVIwould provide XIX. Conversion of XIX using the conditions previouslydescribed for VI, XII and XVII would give compounds of the formula IId.

Heterocycles of the formula XII can also be prepared according to theprocedure described in Scheme 6. Imide XXI can be prepared by theacylation of amide XX using the procedure described by, but not limitedto, Hansen, M. M., et al., Tetrahedron Letters, Vol. 36. 1995, pp.8949-8952. Imide XXI is then converted to unsaturated imide XXII bysulfenylation and oxidative elimination according to the proceduresdescribed in, but not limited to, Zoretic, P. A., et al., Journal ofOrganic Chemistry, Vol. 41, 1976, pp. 3587-89 and Torisawa, Y., et al.,Journal of Organic Chemistry, Vol. 57, 1992, pp. 5741-5747, respectively. The R⁵ substituent can then be introduced using methods described inScheme 4 for the conversion of XV to XVI. Imide XXIII can then beconverted to heterocycle XII (via the intermediacy of XXIV) using thesequence described in Scheme 2 for the conversion of IV (via V) to VI.

Heterocycles of the formula VI, XII, XVII and XIX can also be preparedby the sequence described in Scheme 7. Aldehydes of the formula XXVa-dcan be converted to acyl iminium ion precursors using the conditionsdescribed by, but not limited to, Speckamp, W. N. et al, in“Comprehensive Organic Synthesis” B. M. Trost, Editor, Volume 2, pp.1047-1082. The resulting protected lactamols of the formula XXVIa-d canalso be prepared from amino acids of the formula XXVIIa-d. Cyclizationof XXVIIa-d using conditions previously described for, but not limitedto, IIa-d (Scheme 1, March, 4th. Ed. pp. 419-421) followed by partialreduction of the resulting imide (see the synthesis of V and XXIII,Scheme 2 and 6, respectively) and subsequent protection of the lactamolwill provide XXVIa-d.

The resulting lactamols (or their protected counterparts) can then betransformed into compounds of the formula VI, XII, XVII and XIX usingconditions previously described for V (Scheme 2) or XXIV (Scheme 6).Acyclic precursors of the formula XXVa-d and XXVIIa-d can be preparedusing methods know to those skilled in the art of organic synthesis.

Compounds of Formula XXIXa-d can be prepared by the method depicted inScheme 8. The quaternary salts can be synthesized according to themethods described by, but not limited to, March, 4th Ed., pp. 411-413.The N-oxides of Formula XXIXa-d can be synthesized according to themethods described by, but not limited to, March, 4th Ed., pp. 1200-1201.

The compounds of this invention and their preparation can be furtherunderstood by the following working examples. These examples are meantto be illustrative of the present invention and are not meant to betaken as limiting thereof.

EXAMPLE 1

(+)-N-(3-cyanophenyl)-N′-{[3-(2S,4R)-4-(benzyl)piperidinyl]propyl}ureaand

(−)-N-(3-cyanophenyl)-N′-{[3-(2R,4S)-4-(benzyl)piperidinyl]propyl}urea

Step 1

To a −23° C. solution of 4-methoxypyridine (45.8 mmol) in 200 mL of THFwas added dropwise phenylchloroformate (50.4 mmol). The resulting slurrywas stirred at this temperature for 1 hour. After cooling to −78° C.,allylmagnesium chloride was added dropwise and the resulting solutionstirred at this temperature for 2 hours. The reaction was then quenchedby the addition of 40 mL of 1N HCl, warmed to room temperature andstirred for 12 hours. The resulting aqueous layer was extracted withEtOAc (3 times). The combined organic layer was washed successively withsaturated NaHCO₃ and brine. The resulting solution was dried overmagnesium sulfate, filtered, and concentrated in vacuo. The remainingoil was purified using flash chromatography (silica, 0-50%EtOAc/hexanes) to give 7.2 g of 1 (Scheme 9). ¹³C NMR (CDCl₃) δ 35.4,39.5, 53.1, 108.1, 119.4, 121.2, 126.4, 129.6, 132.8, 141.0, 150.5,182.4, 192.5 ppm. Mass spectrum [NH₃/CI], [(M+H)⁺]=258.

Step 2

To a solution of 1 (6.40 g) in 60 mL of methanol was added 6.3 mL of a25% solution of sodium methoxide in methanol. The resulting solution waswarmed to reflux for 30 minutes and then cooled to room temperature. ThepH of the solution was adjusted to a pH of seven by the careful additionof the appropriate amount of 1 N HCl. The resulting solution wasconcentrated in vacuo and the remaining aqueous layer extracted withether (3 times). The aqueous layer was freeze dried, suspended in EtOAc,filtered and concentrated in vacuo. The ether layer was concentrated invacuo and the residue purified by column chromatography (silica, 50%EtOAc/hexanes then 0-10% MeOH/CH₂Cl₂). The two resulting oils (2) (3.1g) were combined and dissolved in acetonitrile (50 mL). This reactionmixture was charged with Boc₂O (1.28 g) and 4-dimethylamino pyridine(0.024 g) and stirred for one hour. It was then diluted with EtOAc andwashed successively with 1N HCl, saturated NaHCO₃ and brine. The organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by flash chromatography (silica, 0-50%EtOAc/hexanes) to give 5.9 g of 3. ¹³C NMR (CDCl₃) δ 27.9, 35.0, 39.2,52.3, 83.2, 106.1, 118.7, 133.1, 141.8, 151.1, 192.6 ppm. Mass spectrum[NH₃/CI], [(M+H)⁺]=238.

Step 3

To a solution of 3 (6.73 g) in 60 mL of THF at −78° C. was addeddropwise lithium-tri-sec-butyl borohydride (31.2 mL of a 1M THFsolution) over a 15 minute period. The resulting solution was stirred at−78° C. for an additional 60 minutes, quenched by the dropwise additionof water and warmed to room temperature. Concentration in vacuo followedby purification using flash chromatography (silica, 0-50% EtOAc/hexanes)provided 4.98 g of 4. ¹³C NMR (CDCl₃) δ 28.3, 37.2, 38.4, 40.5, 44.5,51.6, 80.4, 118.1, 133.5, 154.6, 208.0 ppm. Mass spectrum [NH₃/CI],[(M+H)⁺]=240.

Step 3a

Alternatively, enone 3 can be reduced by the following procedure. To asolution of enone 3 (18.7 g, 78.8 mmol) in 180 mL of glacial acetic acidwas added in small portions Zn dust (278 mmol) so that the internaltemperature never rises above 50° C. After complete addition of themetal, the reaction was allowed to stir 12 h at 45° C. After cooling toroom temperature the reaction mixture was filtered and the zinc saltswashed with 5-15 mL portions of EtOAc. Concentration of the combinedorganic layers in vacuo followed by purification using flashchromatography (silica, 20% EtOAc/hexanes) provided 17.1 g of ketone 4.

Step 4

To a suspension of benzyltriphenyl phosphonium chloride (32.2 g) in 75mL of THF was added 79 mL (1M in THF) of potassium t-butoxide. Afterstirring at room temperature for 20 minutes, ketone 4 was added dropwisein 100 mL of THF. The resulting solution was stirred for 12 hours. Thereaction was then quenched by the addition of 2N HCl and poured intoether. The aqueous layer was extracted twice with ether. The combinedorganic layer was washed successively with saturated NaHCO₃ and brine.The resulting solution was then dried over magnesium sulfate, filteredand concentrated in vacuo. The residue was slurried in hexanes, filteredand concentrated in vacuo. Purification using flash chromatography(silica, 0-20% EtOAc/hexanes) provided an approximately 1:1 mixture of Eand Z-5. Mass spectrum [NH₃/CI], [(M+H)⁺]=314.

Step 5

To a solution of 9-BBN dimer (3.48 g) in 40 mL of THF at 0° C. was addeddropwise a mixture of E and Z-5 (6.5 g) in 40 mL of THF. The reactionwas warmed to room temperature and stirred for 75 minutes. The reactionwas then cooled to 0° C., treated with 35 mL of pH=7.2 phosphate bufferand 35 mL of 35% hydrogen peroxide. The resulting mixture was allowed towarm to room temperature and stirred for an additional 1 hour. Thesolution was then concentrated in vacuo and the remaining residuedissolved in ether. The resulting organic layer was washed successivelywith 1N NaHSO₃ and brine. The organic layer was then dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue wasthen purified using flash chromatography (silica, 0-50% EtOAc/hexanes)to provide 6.85 g of an approximately 1:1 mixture of E and Z-6 (Scheme10). Mass spectrum [ESI], [(M+H)⁺]=332.

Step 6

To a solution of approximately 100 mL of dry doubly-distilled ammonia at−78° C. was added 66 mL of THF and 733 mg of lithium metal. Theresulting solution was allowed to stir for 20 minutes and then 3.42 g ofa mixture of E and Z-6 was added dropwise in 33 mL of THF. The reactionwas then quenched by the slow addition of ammonium chloride and warmedto room temperature. After stirring for 60 minutes the residue waspoured into ether and washed successively with water and brine. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification using flash chromatography (silica,0-35% EtOAc/hexanes) provided 2.43 g of 7t. ¹³C NMR (DMSO, d₆, 90° C.) δ25.9, 27.7, 29.1, 31.3, 34.6, 37.8, 42.3, 49.8, 60.2, 77.8, 125.2,127.6, 128.4, 139.5, 153.7 ppm. Mass spectrum [ESI], [(M+H)⁺]=334.

Step 7

To a solution of alcohol 7t (2.43 g) in 20 mL of anhydrous pyridine at0° C. was added p-toluenesulfonyl chloride (2.1 g). The reaction mixturewas then slowly warmed to room temperature and stirred for 5 hours. Theresulting solution was concentrated in vacuo and poured into a largevolume of ether. The organic layer was washed successively with 1 N HCl(3 repetitions), saturated NaHCO₃ and brine. The resulting solution wasdried over magnesium sulfate, filtered and concentrated in vacuo. Theremaining oil was purified using flash chromatography (silica, 0-25%EtOAc/hexanes) to give 2.86 g of 8t. ¹³C NMR (CDCl₃) δ 21.6, 25.8, 26.2,28.4, 31.8, 32.5, 35.9, 37.8, 43.4, 49.7, 70.2, 79.2, 126.0, 127.8,128.2, 129.0, 129.8, 133.1, 139.9, 144.7, 154.8 ppm. Mass spectrum[ESI], [(M+H)⁺]=488.

Step 8

To a solution of tosylate 8t in 30 mL of anhydrous DMSO was added sodiumazide (1.9 g). The resulting slurry was stirred for 18 hours. Thereaction mixture was diluted with a partially saturated mixture ofsodium chloride and then poured into ether. The aqueous layer was thenextracted with ether (three repetitions). The combined organic layer waswashed with a partially saturated solution of sodium chloride. Theremaining organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification by flash chromatography (silica,0-10% EtOAc/hexanes) provided 1.95 g of 9t. ¹³C NMR (CDCl₃) δ 25.6,27.5, 28.5, 31.7, 32.6, 35.6, 38.5, 43.5, 49.9, 51.1, 79.4, 126.0,128.2, 129.1, 140.0, 154.9 ppm. Mass spectrum [NH₃/CI], (M+H)⁺=359.

Step 9

A solution of azide 9t in ethyl acetate (30 mL) was treated with 10%palladium on carbon (0.500 g) and stirred under an atmosphere ofhydrogen gas for two hours. Filtration through celite and concentrationin vacuo gave crude amine 10t.

Step 10

To a 0° C. solution of crude amine 10t (1.3 g) in THF (30 mL) was added3-cyanophenyl isocyanate (4.08 mmol) dropwise in 5 mL of THF.Concentration in vacuo followed by flash chromatography provided 1.35 gof 11t. ¹³C NMR (CDC1, ) δ 14.1, 22.6, 25.3, 28.2, 28.5, 31.5, 31.8,32.3, 35.4, 39.5, 40.2, 43.3, 49.8, 80.3, 112.6, 118.9, 121.4, 122.6,125.3, 126.0, 128.3, 129.0, 129.7, 139.7, 140.7, 155.3, 155.9 ppm. Massspectrum [ESI], [(M+Na)⁺]=499.

Step 11

Urethane 11t (1.3 g) was dissolved in 25 mL of 4M HCl in dioxane andstirred for 2 hours. The resulting solution was concentrated in vacuo toprovide 1.17 g of 12t. ¹³C NMR (CDCl₃) δ 14.1, 22.6, 25.5, 26.1, 30.7,31.1, 31.5, 36.7, 38.7, 40.3, 51.8, 112.9, 118.6, 121.5, 123.3, 125.7,126.6, 128.6, 128.7, 128.9, 130.1, 139.1, 140.7, 157.7 ppm. Massspectrum [ESI], [(M+H)⁺]=377.

Resolution 1

The enantiomers of 12t can be resolved by HPLC using the followingconditions.

Mixture A: 98% acetonitrile, 1% ethanol, 0.9% methanol, 0.1% diethylamine; Mixture B: 50% ethanol, 50% methanol; Eluting solvent mixture:94% Mixture A: 6% Mixture B; Flow rate: 1 mL/min; Injection solvent: 94%Mixture A: 6% Mixture B; Column: Chiral Pak AD (4.6 mm×250 mm)

The hydrogen chloride salt of (+) and (−)-12t can be regenerated bydissolving the respective free base in CH₂Cl₂ and adding one equivalentof 1N HCl in ether. The resulting solution can be concentrated in vacuoto provide (+)-12t ([α]_(D) ²⁵=+8.6°, c=0.488, CH₃OH) and (−)-12t([α]_(D) ²⁵=−7.20°, c=0.426, CH₃OH).

EXAMPLE 2

(±)-cis-N-(3-cyanophenyl)-N′-{[3-(4-(benzyl)-2-piperidinyl]propyl}urea

Step 12

A deoxygenated ethanolic solution of an approximately 1:1 mixture of Eand Z-6 (0.072 g) was charged with 0.026 g of 10% Pd on carbon andallowed to stir under an atmosphere 1.5:1 mixture of 7c and 7t,respectively.

of hydrogen gas for 12 hours. Filtration through celite andconcentration in vacuo provided 0.065 g of an approximately Conversionof this mixture of alcohols using steps 7-10 from example 1 provided anapproximately 1.5:1 mixture of 11c and 11t, respectively (Scheme 11.)

Separation 1

Separation of 11c and 11t could be accomplished by high performanceliquid chromatography (column: silica; [41.5 mm (diameter)×25 cm(length)]; solvent: 1% methanol/methylene chloride; flow rate: 45mL/min; detector wavelength: 260 nm). Retention time: 11c 24.6 minutes,11t=27.3 minutes.

Step 13

To a 0° C. solution of 11c in 2 mL of CH₂Cl₂ was added dropwise 2 mL ofTFA. Concentration in vacuo after 2 hours provided 12c. Mass spectrum[ESI], [(M+H)⁺]=377.

EXAMPLE 3

(±)-trans-N-(3-cyanophenyl)-N′-[3-[4-(4-fluorobenzyl)-2-piperidinyl]propylurea

The above compound was prepared by substituting 4-fluoro benzyltriphenylphosphonium chloride in step 4 (example 1), then performing step 5, step12, steps 7-10, separation 1 and step 12. Mass spectrum [ESI],[(M+H)⁺]=395.

EXAMPLE 4

(±)-trans-N-(3-cyanophenyl)-N′-[3-[4-(4-benzyl)-1-methyl-2-piperidinyl]propylurea

To a solution of (±)-12t (0.006 g) in 1 mL of 1,2-dichloroethane wasadded a drop of formaldehyde and 0.050 g of crushed 4A molecular sieves.After stirring for 15 minutes, an excess (0.050 g) of sodiumtriacetoxyborohydride was added and the mixture stirred for anadditional 12 hours. The reaction mixture was then quenched by theaddition of 1 N NaOH and poured into EtOAc. The resulting organic layerwas dried over magnesium sulfate filtered and concentrated in vacuo.Purification by reverse phase chromatography provided the TFA salt ofthe above compound. Mass spectrum [ESI], [(M +H)⁺]=391.

EXAMPLE 5

(±)-trans-N-(3-cyanophenyl)-N′-[3-[4-(4-benzyl)-1-acetyl-2-piperidinyl]propylurea

To a solution of (±)-12t (0.006 g) in 1 mL of CH₂Cl₂ was added an excess(0.050 mL) of acetic anhydride and triethyl amine (0.050 mL). Afterstirring for 15 minutes the solution was poured into EtOAc and washedwith 1 N HCl, saturated NaHCO₃ and brine. The organic layer was driedover magnesium sulfate, filtered, and concentrated in vacuo.Purification by flash chromatography (0-4% CH₂Cl₂/MeOH) provided theabove compound. Mass spectrum [ESI], [(M+H)⁺]=419.

EXAMPLE 47

N-(3-acetylphenyl)-N′-{[3-(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea

Ketone 17 (the S-enantiomer of ketone 4, see Scheme 9) can be preparedby a slight modification of the procedure described in Example 1.

To a −23 ° C. solution of 2-tri-i-propylsilyl-3-methoxy pyridine (65.5g, 247 mmol) in 1.5 mL of toluene and 400 mL of anhydrous THF was added1.7 L of a 0.16 M solution of B in toluene. The resulting solution wasstirred for 2 h and then cooled to −78 ° C. To this solution was addeddropwise 247 mL of a 2 M THF solution of allyl magnesium chloride. Afterstirring for 1 h at this temperature the reaction was quenched with 3 Lof 1 N HCl and stirred at room temperature for 12 h. After separatingthe two phases, the aqueous layer was washed with Et₂O and combined withthe original organic layer. This combined layer was washed with brineand dried over magnesium sulfate. Concentration, chromatography (silica,5% EtOAc/hexanes) and recrystalization from hot hexanes provided enone13.

Enone 13 was dissolved in 360 mL of a 75% solution of TFA in CH₂Cl₂ andstirred for 10 h. Concentration, reconcentration from methanol andchromatography (silica, 20% EtOAc/hexanes) of the residue provided enone14.

To a solution of enone 14 in 1 L of methanol was added 70 g of potassiumcarbonate. After stirring for 4 h at reflux, the reaction was cooled toroom temperature, concentrated, slurried in EtOAc and filtered. Theresulting solution was concentrated and the residue chromatographed(silica, 20% MeOH/EtOAc) to provide vinylogous amide 15.

To a solution of amide 15 (30 g) in 1 L of acetonitrile was added DMAP(35.4 g) and Boc₂O. After stirring for 12 h, the reaction mixture wasconcentrated and diluted with EtOAc. The resulting solution was washedwith 1 N HCl, saturated NaHCO₃ and brine. The remaining solution wasthen dried over magnesium sulfate, filtered, and concentrated in vacuo.Purification by flash chromatography (20% EtOAc/hexanes) provided enone16. Reduction of enone 16 using the method described in Example 1, Step3a provided ketone 17. Mass spectrum [NH₃/CI], [(M+H)⁺]=240; ([α]_(D)²⁵=+36.9°, c=0.396, CH₃OH); ¹³C NMR (CDCl₃) δ 28.3, 37.2, 38.4, 40.5,44.5, 51.6, 80.4, 118.1, 133.5, 154.6, 208.0 ppm.

To a −78° C. solution of A (65 g, 121 mmole, see Scheme 14) in 250 mL ofTHF was added dropwise 241 mL of a 1M KOt-Bu solution (Scheme 13). Aftercomplete addition of the base the reaction mixture was slowly warmed toroom temperature

and stirred for 1 h. Ketone 17 (17 g, 17 mmole) was then added dropwisein 50 mL of THF and the solution stirred until the completedisappearance of starting ketone. The reaction mixture was quenched bythe addition of 1N HCl. The organic layer was washed with saturatedNaHCO₃ and brine. The remaining solution was then dried over magnesiumsulfate, filtered, and concentrated in vacuo. Purification by flashchromatography (0-20% EtOAc/hexanes) provided a mixture of olefins 18(Scheme 13.)

Reduction of this mixture of olefins 18 according to the conditionsdescribed in Example 1, Step 6 provided olefin 19t. To a −78° C.solution of 70% HF/pyridine (39 mL) was slowly added a solution of 19t(13.4 g, 40.4 mmole) in 13 mL of pyridine. The resulting solution wasallowed to stabilize at −30° C. (internal temperature) after whichsodium nitrite (5.6 g, 81 mmole) was added in one portion. The reactionmixture was allowed to stir at −10° C. for 30 min after which 4.9 g ofurea was added and the temperature allowed to rise to 0° C. Afterstirring for 30 min, the temperature was raised to 50° C. and themixture stirred until all signs of gas evolution had ceased.

After cooling to 0° C. the reaction was quenched by the careful additionof 1 N NaOH and then diluted with a large portion of EtOAc. Theresulting aqueous layer was exhaustively extracted with additionalEtOAc. The combined organic layers were concentrated in vacuo anddissolved in dioxane (80 mL). To this solution was added Boc₂O (13.2 g)and 1 N NaOH (60 mL). After stirring for 1 h the reaction mixture wasconcentrated and dissolved in Et₂O. The organic layer was washed withsaturated NaCl. This solution was then dried over magnesiumsulfate,filtered, and concentrated in vacuo. Purification by flashchromatography (0-10% EtOAc/hexanes) provided 20t. Hydroboration of 20tusing the conditions described in Example 1, Step 5 provided alcohol21t. Preparation of the amine via the tosylation, azide displacement andreduction protocol provided amine 25t. For amine 25t ([α]_(D) ²⁵=+29.2°,c=0.896, CH₃OH); ¹³C NMR (CDCl₃) δ 27.8, 28.5, 30.5, 32.0, 32.6, 35.3;38.5, 42.0, 42.7, 50.3, 79.2, 115.0, 130.3, 135.7, 155.0, 161.3 ppm. Toa 0° C. solution of amine 25t (4 mmol) in THF (20 mL) was added3-acetylphenyl isocyanate (0.562 mL). Concentration in vacuo followed byflash chromatography (silica, 0-60% EtOAc/hexanes) provided crude 26t.To a solution of 26t in 5 mL of CH₂Cl₂ was added 15 mL oftrifluoroacetic acid. After stirring for 2 h the solution wasconcentrated and then reconcentrated from methanol (10 mL). Purificationusing flash chromatography (silica, 0-12% methanol/CH₂Cl₂/NH₄OH, lowerlayer) provided Example 47. ([α]_(D) ²⁵=+5.7°, c=0.474, CH₃OH); ¹³C NMR(CDCl₃) δ 25.4, 25.6, 26.4, 28.1, 30.9, 31.2, 37.8, 38.6, 39.3, 51.7,114.7, 118.2, 121.9, 123.2, 128.7, 130.2, 135.4, 137.5, 140.2, 156.7,161.5, 199.1 ppm.

Salt A

To 23 mL of benzyl alcohol (222 mmol) was added a small piece of lithiummetal (8 mg). The solution was heated with vigorous stirring until allof the metal was consumed and then allowed to cool to room temperature.The resulting solution was diluted with 800 mL of diethyl ether afterwhich a solution of p-chloromethylphenyl isocyanate (34 g, 202 mmol) in200 mL of EtOAc was added over 5 min. The resulting reaction mixture wasstirred for 12 h and then quenched by

the addition of water. The organic layer was washed with saturated NaCl,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresulting solid was washed with generous portions of hexanes and usedwithout further purification. To a slurry of the resulting chloride inbenzene (250 mL) was added triphenyl phosphine (160 g). This mixture washeated for 12 h at reflux and then cooled to room temperature.Filtration provided phosphonium salt A which was used without furtherpurification.

EXAMPLE 48

N-(3-acetylphenyl)-N′-{[3-(2S,4R)-4-(4-fluorobenzyl)1-propylpiperidinyl]propyl}urea

To a solution of the compound prepared in Example 47 (0.077 g) in 2 mLof CH₂Cl₂ was added 0.140 mL of a 1 M solution of HCl in diethyl ether.The mixture was diluted with 5 mL of hexane and concentrated. Theprecipitate was dissolved in 5 mL of 1,2-dichloroethane and charged with0.022 g of propionaldehyde and 0.053 g of sodium triacetoxy borohydride,respectively. After stirring for 30 min. the reaction was quenched with0.100 mL of 1N NaOH and concentrated. Purification using flashchromatography (silica, 0-3% methanol/CH₂Cl₂/NH₄OH, lower layer)provided Example 48. ¹³C NMR (CDCl₃) δ 11.3, 18.7, 23.1, 26.9, 28.3,30.8, 31.1, 39.8, 41.0, 47.8, 55.4, 59.4, 115.8, 119.2, 123.5, 124.9,130.3, 131.6, 136.7, 138.5, 141.1, 157.6, 162.2, 202.0 ppm.

EXAMPLE 65

N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-hydroxyethyl)piperidinyl]propyl}guanidine

To a slurry of 3,5-diacetyl aniline (20 g) (see P. Ulrich, J. Med.Chem., 1984, 27, 35-40 for the preparation of this substance) inacetonitrile (150 mL) was added diphenyl-cyanocarbonimidate (26.9 g).The resulting mixture was heated at reflux for 6 h and allowed to coolto room temperature. The resulting soild was filtered, washed withhexanes and used without further purification.

To a solution of amine 24t (0.617 g) in 35 mL of isopropanol was added0.680 g of the above reagent. The reaction was heated at reflux for 6 h,cooled to room temperature, concentrated and purified by flashchromatography to provide 0.532 g of the resulting cyanoguanidine.

To a solution of the cyanoguanidine (0.532 g) in 5 mL of methylenechloride was added 5 mL of 4N HCl in dioxane at room temperature. After1 h the reaction mixture was concentrated and purified by flashchromatography (silica, 0-10% methanol/CH₂Cl₂/NH₄OH, lower layer) toprovide 0.334 g of Example 65.

The following table (Table 1) contains examples of the presentinvention, which may be prepared by procedures described herein, ormethods familiar to one skilled in the art.

TABLE 1 Core

Linker X-Y

STEREO- EXAMPLE NAME CHEMISTRY X-Y R⁵ R R¹ MASS SPECTRA (ESI) 6(±)-cis-N-{3-[4- benzyl-2- piperidinyl) propyl)-N′ (3-cyanophenyl) ureacis b

H

[M + H]⁺ = 377.5 7 (±)-trans-N-(3- cyanophenyl)-N′-[2-[4- (benzyl)-2-piperidinyl] ethyl urea trans a

H

[M + H]⁺ = 363.48 8 (±)-trans-N{3-[4- benzyl-2- piperidinyl]propyl}-3-cyanobenzamide trans b

H

[M + H]⁺ = 362.49 9 (±)-trans-N-(3- acetylphenyl)-N′-[2-[4- (benzyl)-2-piperidinyl] ethyl urea trans a

H

[M + H]⁺ ⁼380.51 10 (±)-trans-N{3-[4- benzyl-2- piperidinyl]propyl)-4-fluorobenzenesulfonamide trans b

H

[M + H]⁺ = 391.52 11 (±)-trans-N{3-[4- benzyl-2- piperidinyl]propyl}benzamide trans b

H

[M + H]⁺ = 337.48 12 (±)-cis-N-(3- cyanophenyl)-N′-[3-[4-(4-fluorobenzyl)-2- piperidinyl]propyl urea cis b

H

[M + H]⁺ = 395.5 13 (±)-trans-N-(3- acetylphenyl)-N′-[3-[4-(4-fluorobenzyl)-2- piperidinyl]propyl urea trans b

H

[M + H]⁺ = 412.52 14 (±)-cis-N-(3- acetylphenyl)-N′-[3-[4-(4-fluorobenzyl)-2- piperidinyl]propyl urea cis b

H

[M + H]⁺ = 412.52 15 (±)-trans-N-(3- chlorophenyl)-N′-[3-[4- (benzyl)-2-piperidinyl]propyl urea trans b

H

[M + H)⁺ = 386.94 16 (±)-trans-N-(phenyl)- N′-[3-[4-(benzyl)-2-piperidinyl]propyl urea trans b

H

[M + H]⁺ = 352.5 17 (±)-trans-N-(3- fluorophenyl)-N′-[3-[4- (benzyl)-2-piperidinyl]propyl urea trans b

H

[M + H]⁺]= 387.56 18 (±)-trans-N-(3- methoxyphenyl)-N′-[3-[4-(benzyl)-2- piperidinyl)]propyl urea trans b

H

[M + H]⁺ = 382.52 19 (±)-trans-N-(4- carboethoxyphenyl)-N′-[3-[4-(benzyl)-2- piperidinyl]propyl urea trans b

H

[M + H]⁺ = 424.56 20 (±)-trans-N-(4- fluorophenyl)-N′-[3-[4- (benzyl)-2-piperidinyl]propyl urea trans b

H

[M + H]⁺ = 370.49 21 (±)-trans-N-(3- acetylphenyl)-N′-[3-[4- (benzyl)-2-piperidinyl]propyl urea trans b

H

[M + H]⁺ = 394.53 22 (±)-trans -N-(3- trifluoromethylphenyl)-N′-[3-[4-(benzyl)-2- piperidinyl]propyl urea trans b

H

[M + H]³⁰ = 420.49 23 (±)-cis-N-(3- cyanophenyl) -N′-[3-[4-(benzyl)-1-propyl-2- piperidinyl]propyl urea cis b

CH2CH2CH3

[M + H]⁺ = 419.59 24 (±)-trans-N-(3- acetylphenyl)-N′-[3-[4-(benzyl)-1-propyl-2- piperidinyl]propyl urea trans b

CH2CH2CH3

[M + H]⁺ = 436.61 25 (±)-cis-N-(3- acetylphenyl)-N′-[3-[4(4-fluorobenzyl)-1- propyl-2- piperidinyl]propyl urea cis b

CH2CH2CH3

[M + H]⁺ = 454.6 26 (±)-trans-N-(3- acetylphenyl)-N′-[3-[4(4-fluorobenzyl)-1- propyl-2- piperidinyl]propyl urea trans b

CH2CH2CH3

[M + H]⁺ = 454.6 27 (±)-trans-N{2-[4- benzyl-2- piperidinyl)ethyl)-4-fluorobenzenesulfonamide trans a

H

[M + H]⁺ = 377.5 28 (±)-trans-N{2-[4- benzyl-2- piperidinyl]ethyl}-3-chlorobenzenesulfonamide trans a

H

[M + H]⁺ = 393.95 29 (±)-trans-N{2-[4- benzyl-2- piperidinyl}ehtyl)-3-cyanobenzamide trans a

H

[M + H]⁺ = 348.46 30 (±)-trans-N-(3- cyanophenyl)-N′-[4-[4- (benzyl)-2-piperidinyl]butyl urea trans c

H

[M + H]⁺ = 391.53 31 (±)-trans-N-(3- acetylphenyl)-N′-[4-[4- (benzyl)-2-piperidinyl]butyl urea trans c

H

[M + H]⁺ = 406.56 32 N-(3-acetylphenyl)-N′- {[3-[2S, 4S]-4-(4-fluorobenzyl)piperidin yl]propyl} urea 2S, 4S b

H

[M + H]⁺ = 412.518 33 N-(3-acetylphenyl)-N′- {[4-[2R, 4R]-4-(4-fluorobenzyl)-2- piperidinyl]butyl } urea 2R, 4R c

H

[M + H]⁺ = 426.545 34 N-(3-cyanophenyl)-N′- {[4-[2R, 4R]-4-(4-fluorobenzyl)piperidin yl]butyl} urea 2R, 4R c

H

[M + H]⁺ = 409.518 35 N-(3-acetylphenyl)-N′- {3-[(2S,4R)-4-(2,4-difluorobenzyl)piperidinyl] propyl}urea 2R, 4R b

H

[M + H]⁺ = 430.508 36 N-{3-[(2S, 4R)-1-allyl-4-(4-fluorobenzyl)piperidinyl] propyl}-N′-(3,5- diacetylphenyl)urea 2S,4R b

CH2CHCH2

[M + H]⁺ = 494.619 37 N-(3,5-diacetylphenyl)- N′-{3-[(2S, 4R)-4-(4-fluorobenzyl)-1-(2- hydroxyethyl)piperidinyl] propyl}urea 2S, 4R b

CH2CH2OH

[M + H]⁺ = 498.607 38 N-{3-[(2S, 4R)-1-acetyl 4-(4-fluorobenzyl)piperidinyl] propyl}-N′-(3,5- diacetylphenyl)urea 2S, 4R b

C(O)CH3

[M + H]⁺ = 496.592 39 N-(3,5-diacetylphenyl)- N′-{3-[(2S)-4-(4-fluorobenzyl)-1-(2- fluoroethyl)piperidinyl] propyl}urea 2S, 4R b

CH2CH2F

[M + H]⁺ = 500.599 40 (±)-trans-N-(3- acetylphenyl)-N′-{3-[4-(benzyl)-1-(2- hydroxyethyl)-2- piperidinyl}propyl urea trans b

CH2CH2OH

[M + H]⁺ = 438.59 41 (±)-trans-N-(3- acetylphenyl)-N′-[3-[4-(benzyl)-1-methyl-2- piperidinyl]propyl urea trans b

CH3

[M + H]⁺ = 408.56 42 (±)-trans-N-(3- acetylphenyl)-N′-[3-[4-(benzyl)-1-ethyl-2- piperidinyl]propyl urea trans b

CH2CH3

[M + H]⁺ = 422.59 45 N-(3-acetylphenyl)-N′- {[3-(2R, 4R)-4-(4-fluorobenzyl)piperidinyl] propyl}urea 2R, 4R b

H

[M + H]⁺ = 412.518 46 N-(3-acetylphenyl)-N′- {[3-(2S, 4R)-4-(4-fluorobenzyl)piperidinyl] propyl} urea 2S, 4R b

H

[M + H]⁺ = 412.518 47 N-(3-acetylphenyl)-N′- {[3-(2S, 4R)-4-(4-fluorobenzyl)1- propylpiperidinyl]propyl} urea 2S, 4R b

CH2CH2CH3

[M + H]⁺ = 454.598 48 N-(3-acetylphenyl)-N′- {[3-(2S, 4R)-4-(4-fluorobenzyl)1- methylpiperidinyl] propyl} urea 2S, 4R b

CH3

[M + H]⁺ = 426.545 49 N-(3-acetylphenyl)-N′- {[3-(2S, 4R)-4-(4-fluorobenzyl)-1-(2- hydroxyethyl)piperidinyl] propyl} urea 2S, 4R b

CH2CH2OH

[M + H]⁺ = 456.571 50 [(2S, 4R)-2-(3-{[(3- acetylanilino)carbonyl]amino)propyl)-4-(4- fluorobenzyl)piperindinyl] acetic acid 2S, 4R b

CH2CO2H

[M + H]⁺ = 470.554 51 N-(3-acetylphenyl)-N′- {3-[(2S, 4R)-1-benzyl-4-(4-fluorobenzyl) piperidinyl]propyl}urea 2S, 4R b

[M + H]⁺ = 502.642 52 (±)-trans-N-(3-[(4- benzyl-2-piperidinyl]propyl}-N′- (3-fluoro-4- methylphenyl)urea trans b

H

[M + H]⁺ = 384.508 53 (±)-trans-N-{3-[4- benzyl-2- piperidinyl)propyl}-N′-(3,4- dimethoxyphenyl) urea trans b

H

[M + H]⁺ = 412.543 54 (±)-trans-N-{3-[4- benzyl-2-piperidinyl]propyl}-N′- (6-methoxy-3- pyridinyl)urea trans b

H

[M + H]⁺ = 383.505 55 (±)-trans-N-{3-[4- benzyl-2-piperidinyl]propyl}-N′- (1H-indazol-6-yl) urea trans b

H

[M + H]⁺ = 392.516 56 N-(3-acetylphenyl)-N′- {3-[(2S, 4R)-1-(cyclopropylmethyl)-4- (4-fluorobenzyl) piperidinyl]propyl}urea 2S, 4R b

[M + H]⁺ = 466.609 57 N-(3-cyanophenyl)-N′- {3-[(2S, 4R)-4-(4-fluorobenzyl)piperidinyl] propyl}urea 2S, 4R b

H

[M + H]⁺ 395.491 58 N-(3-cyanophenyl)-N′- {3-[(2S, 4R)-4-(4-fluorobenzyl)-1- propylpiperidinyl] propyl}urea 2S, 4R b

CH2CH2CH3

[M + H]⁺ = 437.572 59 N-(3-acetylphenyl)-N′- {3-[(2S, 4R)-1-allyl-4-(4-fluorobenzyl) piperidinyl]propyl}urea 2S, 4R b

CH2CHCH2

[M + H]⁺ = 452.583 60 N-{3-[(2S, 4R)-4-(4- fluorobenzyl)piperidinyl]propyl}-N′-[3-(1- methyl-1H-tetraazol-5- yl)phenyl]urea 2S, 4R b

H

[M + H]⁺ = 452.547 61 N-{3-[(2S, 4R)-4-(4- fluorobenzyl)-1-propylpiperidinyl] propyl}-N′-[3-(1-methyl-1H- tetraazol-5-yl)phenyl]urea 2S, 4R b

CH2CH2CH3

[M + H]⁺ = 494.627 62 (2S, 4R)-2-(3-{[(E)- {[(E)-amino(oxo)methyl]imino} (3,5-diacetylanilino)methyl] amino}propyl)-4-(4-fluorobenzyl)-N-methyl-1- piperidinecarboxamide 2S, 4R b

C(O)NHCH3

[M + H]⁺ = 553.647 63 N-[(E)-({3-[(2S, 4R)-1- acetyl-4-(4-fluorobenzyl)piperidinyl] propyl}amino) (3,5- diacetylanilino)methylidene]urea 2S, 4R b

C(O)CH3

[M + H]⁺ = 538.632 64 N′′-cyano-N-(3,5- diacetylphenyl)-N′-{3- [(2S,4R)-4-(4- fluorobenzyl)-1-(2- hydroxyethyl)piperidinyl] propyl}guanidine2S, 4R b

CH2CH2OH

[M + H]⁺ = 522.633 65 N-(3,5-diacetylphenyl)- N′-{3-[(2S, 4R)-4-(4-fluorobenzyl)piperidinyl] propyl}urea 2S, 4R b

H

[M + H]⁺ = 454.555 66 N-(3,5-diacetylphenyl)- N′-{3-[(2S)-4-(4-fluorobenzyl)-1- propylpiperidinyl] propyl}urea 2S, 4R b

CH2CH2CH3

[M + H]⁺ = 496.635 67 N-[(E)-(3,5- diacetylanilino) ({3- [(2S, 4R)-4-(4-fluorobenzyl)piperidinyl] propyl}amino) methylidene]urea 2S, 4R b

H

[M + H]⁺ = 496.596 68 N′′-cyano-N-(3,5- diacetylphenyl)-N′-{3 - [(2S,4R)-4-(4- fluorobenzyl)piperidineyl] propyl}guanidine 2S, 4R b

H

[M + H]⁺ = 478.581 69 (2S, 4R)-2-(3-}[(3,5- diacetylanilino)carbonyl]amino}propyl)-4-(4- fluorobenzyl)-1- piperidinecarboximidamide 2S, 4R b

C(═NH)NH2

[M + H]⁺ = 496.596 70 N′′-cyano-N-(3,5- diacetylphenyl)-N′-(3- [(2S,4R)-4-(4- fluorobenzyl)-1- propylpiperidinyl] propyl}guanidine 2S, 4R b

CH2CH2CH3

[M + H]⁺ = 520.661 71 (2S, 4S)-2-(3-{[(3- acetylanilino)carbonyl]amino}propyl)-4-(4- fluorobenzyl)-1- piperidinecarboximidamide 2S, 4R b

C(═NH)NH2

[M + H]⁺ = 454.559 72 N-{3-[(2S, 4R)-1- (aminoacetyl)-4-(4-fluorobenzyl)piperidinyl] propyl}-N′-(3,5- diacetylphenyl)urea 2S, 4R b

C(O)CH2NH2

[M + H]⁺ = 511.607 73 N-{3-[(2S, 4R)-1-allyl- 4-(4-fluorobenzyl)piperidinyl] propyl}N′′-cyano- N′-(3,5- diacetylphenyl)guanidine 2S, 4Rb

CH2CHCH2

[M + H]⁺ = 518.645 74 N′′-cyano-N-(3,5- diacetylphenyl)-N′-{3- [(2S,4R)-4-(4- fluoroethyl)piperidinyl] propyl}guanidine 2S, 4R b

CH2CH2F

[M + H]⁺ = 524.625 75 N′′-cyano-N-(3,5- diacetylphenyl)-N′-(3- [(2S,4R)-4-(4- fluorobenzyl)-1-(2- propynyl)piperidinyl] propyl}guanidine 2S,4R b

CH2CCH

[M + H]⁺ = 516.63 76 N′′-cyano-N-(3,5- diacetylphenyl)-N′-{3- [(2S,4R)-4-(4- fluorobenzyl)-1- methylpiperidinyl] propyl}guanidine 2S, 4R b

CH3

[M + H]⁺ = 492.608 78 N′′-cyano-N-(3,5- diacetylphenyl)-N′-{3- [(2S,4R)-1-ethyl-4-(4- fluorobenzyl)piperindinyl] propyl}guanidine 2S, 4R b

CH2CH3

[M + H]⁺ = 506.634 79 N-[3,5-bis(1-methyl-1H- tetraazol-5-yl)phenyl]-N′-{3-[(2S, 4R)-4-(4- fluorobenzyl)piperidinyl] propyl}urea 2S, 4R b

H

[M + H]⁺ = 648.635 80 N-{3-[(2S, 4R)-1-acetyl- 4-(4-fluorobenzyl)piperidinyl] propyl}-N′-[3,5- bis(1-methyl-1H- tetraazol-5-yl)phenyl]urea 2S, 4R b

C(O)CH3

[M + H]⁺ = 576.65 81 N-(3,5-diacetylphenyl)- N′-{3-[(2S)-4-(4-fluorobenzyl)-1-(2,2,2- trifluoroethyl)piperidinyl] propyl)urea 2S, 4R b

CH2CF3

[M + H]⁺ = 536.579 82 N-(3,5-diacetylphenyl)- N′-{3-[(2S, 4R)-1-(2,2-difluoroethyl)-4-(4- fluorobenzyl)piperidinyl] propyl}urea 2S, 4R b

CH2CHF2

[M + H]⁺ = 518.589 83 N-(3,5-diacetylphenyl)- N′-{3-[(2S, 4R)-4-(4-fluorobenzyl)-1- (methylsulfonyl)piperidinyl] propyl}urea 2S, 4R b

SO2CH3

[M + H]⁺ = 532.646 84 N-(3,5-diacetylphenyl)- N′-{3-[(2S, 4R)-4-(4-fluorobenzyl)-1- propionylpiperidnyl] propyl}urea 2S, 4R b

C(O)CH2CH3

[M + H]⁺ = 510.618 85 N-(3,5-diacetylphenyl)- N′-{3-[(2S, 4R)-4-(4-fluorobenzyl)-1- isobutyrylpiperidinyl] propyl}urea 2S, 4R b

C(O)CH(CH3)2

[M + H[⁺ = 524.645 86 (2S, 4R)-2-(3-{[(3,5- diacetylanilino)carbonyl]amino}propyl)-4-(4- fluorobenzyl)-N-methyl-1- piperidinecarboxamide2S, 4R b

C(O)NHCH3

[M + H]⁺ = 511.607 87 (2S, 4R)-2-(3-{[(3,5- diacetylanilino)carbonyl]amino}propyl)-4-(4- fluorobenzyl)-1- piperidinecarboxamide 2S, 4R b

C(O)NH2

[M + H]⁺ = 497.58 88 N-(3,5-diacetylphenyl)- N′-{3-[(2S, 4R)-4-(4-fluorobenzyl)-1-(2- pyridinylmethyl)piperidinyl] propyl}urea 2S, 4R b

[M + H]⁺ = 545.667 89 2-[(2S, 4R)-2-(3- {[(3,5- diacetylanilino)carbonyl]amino}propyl)-4-(4- fluorobenzyl)piperidinyl] acetamide 2S, 4R b

CH2C(O)NH2

[M + H]⁺ = 511.607 90 N-{3-[(2S, 4R)-1-[(2S)- 2-aminopropanoyl]-4-(4-fluorobenzyl)piperidinyl] propyl}-N′-(3,5- diacetylphenyl)urea 2S, 4R b

[M + H]⁺ = 525.633 91 N-{3-[(2S, 4R)-1-[(2R)- 2-aminopropanoyl]-4-(4-fluorobenzyl)piperidinyl] propyl}-N′-(3,5- diacetylphenyl)urea 2S, 4R b

[M + H]⁺ = 525.633 92 N-(3,5-diacetylphenyl)- N′-{3-[(2S, 4R)-4-(4-fluorobenzyl)-1-(2- propynyl)piperidinyl] propyl}urea 2S, 4R b

CH2CCH

[M + H]⁺ = 492.604 93 1-(3-{[(E)-1-({3-[(2S)- 4-(4-fluorobenzyl)piperidinyl] propyl}amino)-2- nitroethenyl]amino}phenyl)ethanone 2S, 4R b

H

[M + H]⁺ = 455.543 94 (±)-trans-N-{3-(4- (benzyl)-2-piperidinyl]propyl}-N′- [3-(phenylsulfonyl) phenyl]urea trans b

H

[M + H]⁺ = 492.653 95 (±)-trans-N-(3-[4- (benzyl)-2-piperidinyl]propyl}-N′- [3-chloro-4- (diethylamino)phenyl] urea trans b

H

[M + H]⁺ = 458.058 96 (±)-trans-N-(3-{[({3- [4-benzyl-2-piperidinyl]propyl}amino) Carbonyl]amino} phenyl)acetamide trans b

H

[M + H]⁺ = 409.543 97 (±)-trans-N-{3-[4- benzylpiperidinyl]-2-propyl)-N′-[3-(1- hydroxyethyl)phenyl] urea trans b

H

[M + H]⁺ = 396.544 98 (±)-trans-dimethyl 5- {[({3-[4-benzyl-2-piperidinyl]propyl) amino)carbonyl]amino} isophthalate trans b

H

[M + H]⁺ = 468.563 99 (±)-trans-ethyl 3- {[({3-[4-benzyl-2-piperidinyl]propyl} amino)carbonyl]amino} benzoate trans b

H

[M + H]⁺ = 424.554 100 (±)-trans-N-{3-[4- benzyl-2-piperidinyl]propyl}-N′- (3-chlorophenyl)urea trans b

H

[M + H]⁺ = 386.936 101 N-(3,5-diacetylphenyl)- N′-{3-[(2S, 4R)-4-(4-fluorobenzyl)-1-(2-oxo- propyl)piperidinyl] propyl}urea 2S, 4R b

CH2C(O)CH3

[M + H]⁺ = 510 102 N-[3-(2-{3-[(3,5- diacetylanilinocarbonyl)amino}propyl}-4-(4- fluorobenzyl)-1- piperidinyl)propyl] acetamide 2S,4R b

CH2CH2NHC(O)CH3

[M + H]⁺ = 539 103 N-(3,5-diacetylphenyl)- N′-{3-[(2S, 4R)-4-(4-fluorobenzyl)-1-(3- hydroxypropyl)piperidinyl] propyl}urea 2S, 4R b

CH2CH2CH2OH

[M + H]⁺ = 512 104 N′′-cyano-N-(3,5- diacetylphenyl)-N′-{3- [(2S,4R)-4-(4- fluorobenzyl)-1-(2-oxo- propyl)piperidinyl] propyl}guanidine2S, 4R b

CH2C(O)CH3

[M + H]⁺ = 534 105 N′′-cyano-N-(3,5- diacetylphenyl)-N′-{3- [(2S,4R)-4-(4- fluorobenzyl)-1-(3- hydroxypropyl)piperidinyl]propyl}guanidine 2S, 4R b

CH2CH2CH2OH

[M + H]⁺ = 536

The following Table 2 contains additional representative examples of thepresent invention, and may be prepared by procedures described herein,or methods familiar to one skilled in the art. Each entry in the tableis intended to be paired with each core and linker formulae at the topof the table. For example, Entry 1 in Table 2 is intended to be pairedwith Cores a-e, and X-Y linkers f-n.

TABLE 2* Cores

Linkers X-Y

Entry R⁵ R¹ 1 Ph—CH₂— Ph 2 Ph—CH₂— 3-CN—Ph 3 Ph—CH₂— 3-COCH3—Ph 4Ph—CH₂— 3-CO2Me—Ph 5 Ph—CH₂— 3-CO2Et—Ph 6 Ph—CH₂— 3-CO2H—Ph 7 Ph—CH₂—3-CONH2—Ph 8 Ph—CH₂— 3-CONHMe—Ph 9 Ph—CH₂— 3-F—Ph 10 Ph—CH₂— 3-Cl—Ph 11Ph—CH₂— 3-Br—Ph 12 Ph—CH₂— 3-NO2—Ph 13 Ph—CH₂— 3-NH2—Ph 14 Ph—CH₂—3-NHMe—Ph 15 Ph—CH₂— 3-NMe2—Ph 16 Ph—CH₂— 3-NHCOCH3—Ph 17 Ph—CH₂—3-SO2NH2—Ph 18 Ph—CH₂— 3-SO2NHMe—Ph 19 Ph—CH₂— 3-CF3—Ph 20 Ph—CH₂—3-OCH3—Ph 21 Ph—CH₂— 3-OPh—Ph 22 Ph—CH₂— 3-OCF3—Ph 23 Ph—CH₂— 3-SCH3—Ph24 Ph—CH₂— 3-SOCH3—Ph 25 Ph—CH₂— 3-SO2CH3—Ph 26 Ph—CH₂— 3-OH—Ph 27Ph—CH₂— 3-CH2OH—Ph 28 Ph—CH₂— 3-CHOHCH3—Ph 29 Ph—CH₂— 3-COH(CH3)2—Ph 30Ph—CH₂— 3-CHOHPh—Ph 31 Ph—CH₂— 3-CH3—Ph 32 Ph—CH₂— 3-C2H5—Ph 33 Ph—CH₂—3-iPr—Ph 34 Ph—CH₂— 3-tBu—Ph 35 Ph—CH₂— 3-Ph—Ph 36 Ph—CH₂— 3-CH2Ph—Ph 37Ph—CH₂— 3-CH2CO2Me—Ph 38 Ph—CH₂— 3-(1-piperidinyl)-Ph 39 Ph—CH₂—3-(1-pyrrolidinyl)-Ph 40 Ph—CH₂— 3-(2-imidazolyl)-Ph 41 Ph—CH₂—3-(1-imidazolyl)-Ph 42 Ph—CH₂— 3-(2-thiazolyl)-Ph 43 Ph—CH₂—3-(3-pyrazolyl)-Ph 44 Ph—CH₂— 3-(1-pyrazolyl)-Ph 45 Ph—CH₂—3-(1-tetrazolyl)-Ph 46 Ph—CH₂— 3-(5-tetrazolyl)-Ph 47 Ph—CH₂—3-(2-pyridyl)-Ph 48 Ph—CH₂— 3-(2-thienyl)-Ph 49 Ph—CH₂— 3-(2-furanyl)-Ph50 Ph—CH₂— 4-CN—Ph 51 Ph—CH₂— 4-COCH3—Ph 52 Ph—CH₂— 4-CO2Me—Ph 53Ph—CH₂— 4-CO2Et—Ph 54 Ph—CH₂— 4-CO2H—Ph 55 Ph—CH₂— 4-CONH2—Ph 56 Ph—CH₂—4-CONHMe—Ph 57 Ph—CH₂— 4-CONHPh—Ph 58 Ph—CH₂— 4-NHCONH2—Ph 59 Ph—CH₂—4-F—Ph 60 Ph—CH₂— 4-Cl—Ph 61 Ph—CH₂— 4-Br—Ph 62 Ph—CH₂— 4-NO2—Ph 63Ph—CH₂— 4-NH2—Ph 64 Ph—CH₂— 4-NHMe—Ph 65 Ph—CH₂— 4-NMe2—Ph 66 Ph—CH₂—4-NHCOCH3—Ph 67 Ph—CH₂— 4-SO2NH2—Ph 68 Ph—CH₂— 4-SO2NHMe—Ph 69 Ph—CH₂—4-CF3—Ph 70 Ph—CH₂— 4-OCH3—Ph 71 Ph—CH₂— 4-OPh—Ph 72 Ph—CH₂— 4-OCF3—Ph73 Ph—CH₂— 4-SCH3—Ph 74 Ph—CH₂— 4-SOCH3—Ph 75 Ph—CH₂— 4-SO2CH3—Ph 76Ph—CH₂— 4-OH—Ph 77 Ph—CH₂— 4-CH2OH—Ph 78 Ph—CH₂— 4-CHOHCH3—Ph 79 Ph—CH₂—4-COH(CH3)2—Ph 80 Ph—CH₂— 4-CH3—Ph 81 Ph—CH₂— 4-C2H5—Ph 82 Ph—CH₂—4-iPr—Ph 83 Ph—CH₂— 4-tBu—Ph 84 Ph—CH₂— 4-Ph—Ph 85 Ph—CH₂— 4-CH2Ph—Ph 86Ph—CH₂— 4-CH2CO2Me—Ph 87 Ph—CH₂— 4-(1-piperidinyl)-Ph 88 Ph—CH₂—4-(1-pyrrolidinyl)-Ph 89 Ph—CH₂— 4-(2-imidazolyl)-Ph 90 Ph—CH₂—4-(1-imidazolyl)-Ph 91 Ph—CH₂— 4-(2-thiazolyl)-Ph 92 Ph—CH₂—4-(3-pyrazolyl)-Ph 93 Ph—CH₂— 4-(1-pyrazolyl)-Ph 94 Ph—CH₂—4-(1-tetrazolyl)-Ph 95 Ph—CH₂— 4-(5-tetrazolyl)-Ph 96 Ph—CH₂—4-(2-pyridyl)-Ph 97 Ph—CH₂— 4-(2-thienyl)-Ph 98 Ph—CH₂— 4-(2-furanyl)-Ph99 Ph—CH₂— 2-CN—Ph 100 Ph—CH₂— 2-COCH3—Ph 101 Ph—CH₂— 2-CO2Me—Ph 102Ph—CH₂— 2-CO2Et—Ph 103 Ph—CH₂— 2-CO2H—Ph 104 Ph—CH₂— 2-CONH2—Ph 105Ph—CH₂— 2-CONHMe—Ph 106 Ph—CH₂— 2-F—Ph 107 Ph—CH₂— 2-Cl—Ph 108 Ph—CH₂—2-Br—Ph 109 Ph—CH₂— 2-NO2—Ph 110 Ph—CH₂— 2-NH2—Ph 111 Ph—CH₂— 2-NHMe—Ph112 Ph—CH₂— 2-NMe2—Ph 113 Ph—CH₂— 2-NHCOCH3—Ph 114 Ph—CH₂— 2-SO2NH2—Ph115 Ph—CH₂— 2-SO2NHMe—Ph 116 Ph—CH₂— 2-CF3—Ph 117 Ph—CH₂— 2-OCH3—Ph 118Ph—CH₂— 2-OPh—Ph 119 Ph—CH₂— 2-OCF3—Ph 120 Ph—CH₂— 2-SCH3—Ph 121 Ph—CH₂—2-SOCH3—Ph 122 Ph—CH₂— 2-SO2CH3—Ph 123 Ph—CH₂— 2-OH—Ph 124 Ph—CH₂—2-CH2OH—Ph 125 Ph—CH₂— 2-CHOHCH3—Ph 126 Ph—CH₂— 2-COH(CH3)2—Ph 127Ph—CH₂— 2-CHOHPh—Ph 128 Ph—CH₂— 2-CH3—Ph 129 Ph—CH₂— 2-C2H5—Ph 130Ph—CH₂— 2-iPr—Ph 131 Ph—CH₂— 2-tBu—Ph 132 Ph—CH₂— 2-Ph—Ph 133 Ph—CH₂—2-CH2Ph—Ph 134 Ph—CH₂— 2-CH2CO2Me—Ph 135 Ph—CH₂— 2-(1-piperidinyl)-Ph136 Ph—CH₂— 2-(1-pyrrolidinyl)-Ph 137 Ph—CH₂— 2-(2-imidazolyl)-Ph 138Ph—CH₂— 2-(1-imidazolyl)-Ph 139 Ph—CH₂— 2-(2-thiazolyl)-Ph 140 Ph—CH₂—2-(3-pyrazolyl)-Ph 141 Ph—CH₂— 2-(1-pyrazolyl)-Ph 142 Ph—CH₂—2-(1-tetrazolyl)-Ph 143 Ph—CH₂— 2-(5-tetrazolyl)-Ph 144 Ph—CH₂—2-(2-pyridyl)-Ph 145 Ph—CH₂— 2-(2-thienyl)-Ph 146 Ph—CH₂—2-(2-furanyl)-Ph 147 Ph—CH₂— 2,4-diF—Ph 148 Ph—CH₂— 2,5-diF—Ph 149Ph—CH₂— 2,6-diF—Ph 150 Ph—CH₂— 3,4-diF—Ph 151 Ph—CH₂— 3,5-diF—Ph 152Ph—CH₂— 2,4-diCl—Ph 153 Ph—CH₂— 2,5-diCl—Ph 154 Ph—CH₂— 2,6-diCl—Ph 155Ph—CH₂— 3,4-diCl—Ph 156 Ph—CH₂— 3,5-diCl—Ph 157 Ph—CH₂— 3,4-diCF3—Ph 158Ph—CH₂— 3,5-diCF3—Ph 159 Ph—CH₂— 5-Cl-2-MeO—Ph 160 Ph—CH₂— 5-Cl-2-Me—Ph161 Ph—CH₂— 2-F-5-Me—Ph 162 Ph—CH₂— 2-F-5-NO2—Ph 163 Ph—CH₂—3,4-OCH2O—Ph 164 Ph—CH₂— 3,4-OCH2CH2O—Ph 165 Ph—CH₂— 2-MeO-4-Me—Ph 166Ph—CH₂— 2-MeO-5-Me—Ph 167 Ph—CH₂— 1-naphthyl 168 Ph—CH₂— 2-naphthyl 169Ph—CH₂— 2-thienyl 170 Ph—CH₂— 3-thienyl 171 Ph—CH₂— 2-furanyl 172Ph—CH₂— 3-furanyl 173 Ph—CH₂— 2-pyridyl 174 Ph—CH₂— 3-pyridyl 175Ph—CH₂— 4-pyridyl 176 Ph—CH₂— 2-indolyl 177 Ph—CH₂— 3-indolyl 178Ph—CH₂— 5-indolyl 179 Ph—CH₂— 6-indolyl 180 Ph—CH₂— 3-indazolyl 181Ph—CH₂— 5-indazolyl 182 Ph—CH₂— 6-indazolyl 183 Ph—CH₂— 2-imidazolyl 184Ph—CH₂— 3-pyrazolyl 185 Ph—CH₂— 2-thiazolyl 186 Ph—CH₂— 5-tetrazolyl 187Ph—CH₂— 2-benzimidazolyl 188 Ph—CH₂— 5-benzimidazolyl 189 Ph—CH₂—2-benzothiazolyl 190 Ph—CH₂— 5-benzothiazolyl 191 Ph—CH₂— 2-benzoxazolyl192 Ph—CH₂— 5-benzoxazolyl 193 Ph—CH₂— 1-adamantyl 194 Ph—CH₂—2-adamantyl 195 Ph—CH₂— t-Bu 196 Ph—CH₂— Ph 197 Ph—CH₂— 3-CN—Ph 1984-F—Ph—CH₂— 3-COCH3—Ph 199 4-F—Ph—CH₂— 3-CO2Me—Ph 200 4-F—Ph—CH₂—3-CO2Et—Ph 201 4-F—Ph—CH₂— 3-CO2H—Ph 202 4-F—Ph—CH₂— 3-CONH2—Ph 2034-F—Ph—CH₂— 3-CONHMe—Ph 204 4-F—Ph—CH₂— 3-F—Ph 205 4-F—Ph—CH₂— 3-Cl—Ph206 4-F—Ph—CH₂— 3-Br—Ph 207 4-F—Ph—CH₂— 3-NO2—Ph 208 4-F—Ph—CH₂—3-NH2—Ph 209 4-F—Ph—CH₂— 3-NHMe—Ph 210 4-F—Ph—CH₂— 3-NMe2—Ph 2114-F—Ph—CH₂— 3-NHCOCH3—Ph 212 4-F—Ph—CH₂— 3-SO2NH2—Ph 213 4-F—Ph—CH₂—3-SO2NHMe—Ph 214 4-F—Ph—CH₂— 3-CF3—Ph 215 4-F—Ph—CH₂— 3-OCH3—Ph 2164-F—Ph—CH₂— 3-OPh—Ph 217 4-F—Ph—CH₂— 3-OCF3—Ph 218 4-F—Ph—CH₂— 3-SCH3—Ph219 4-F—Ph—CH₂— 3-SOCH3—Ph 220 4-F—Ph—CH₂— 3-SO2CH3—Ph 221 4-F—Ph—CH₂—3-OH—Ph 222 4-F—Ph—CH₂— 3-CH2OH—Ph 223 4-F—Ph—CH₂— 3-CHOHCH3—Ph 2244-F—Ph—CH₂— 3-COH(CH3)2—Ph 225 4-F—Ph—CH₂— 3-CHOHPh—Ph 226 4-F—Ph—CH₂—3-CH3—Ph 227 4-F—Ph—CH₂— 3-C2H5—Ph 228 4-F—Ph—CH₂— 3-iPr—Ph 2294-F—Ph—CH₂— 3-tBu—Ph 230 4-F—Ph—CH₂— 3-Ph—Ph 231 4-F—Ph—CH₂— 3-CH2Ph—Ph232 4-F—Ph—CH₂— 3-CH2CO2Me—Ph 233 4-F—Ph—CH₂— 3-(1-piperidinyl)-Ph 2344-F—Ph—CH₂— 3-(1-pyrrolidinyl)-Ph 235 4-F—Ph—CH₂— 3-(2-imidazolyl)-Ph236 4-F—Ph—CH₂— 3-(1-imidazolyl)-Ph 237 4-F—Ph—CH₂— 3-(2-thiazolyl)-Ph238 4-F—Ph—CH₂— 3-(3-pyrazolyl)-Ph 239 4-F—Ph—CH₂— 3-(1-pyrazolyl)-Ph240 4-F—Ph—CH₂— 3-(1-tetrazolyl)-Ph 241 4-F—Ph—CH₂— 3-(5-tetrazolyl)-Ph242 4-F—Ph—CH₂— 3-(2-pyridyl)-Ph 243 4-F—Ph—CH₂— 3-(2-thienyl)-Ph 2444-F—Ph—CH₂— 3-(2-furanyl)-Ph 245 4-F—Ph—CH₂— 4-CN—Ph 246 4-F—Ph—CH₂—4-COCH3—Ph 247 4-F—Ph—CH₂— 4-CO2Me—Ph 248 4-F—Ph—CH₂— 4-CO2Et—Ph 2494-F—Ph—CH₂— 4-CO2H—Ph 250 4-F—Ph—CH₂— 4-CONH2—Ph 251 4-F—Ph—CH₂—4-CONHMe—Ph 252 4-F—Ph—CH₂— 4-CONHPh—Ph 253 4-F—Ph—CH₂— 4-NHCONH2—Ph 2544-F—Ph—CH₂— 4-F—Ph 255 4-F—Ph—CH₂— 4-Cl—Ph 256 4-F—Ph—CH₂— 4-Br—Ph 2574-F—Ph—CH₂— 4-NO2—Ph 258 4-F—Ph—CH₂— 4-NH2—Ph 259 4-F—Ph—CH₂— 4-NHMe—Ph260 4-F—Ph—CH₂— 4-NMe2—Ph 261 4-F—Ph—CH₂— 4-NHCOCH3—Ph 262 4-F—Ph—CH₂—4-SO2NH2—Ph 263 4-F—Ph—CH₂— 4-SO2NHMe—Ph 264 4-F—Ph—CH₂— 4-CF3—Ph 2654-F—Ph—CH₂— 4-OCH3—Ph 266 4-F—Ph—CH₂— 4-OPh—Ph 267 4-F—Ph—CH₂— 4-OCF3—Ph268 4-F—Ph—CH₂— 4-SCH3—Ph 269 4-F—Ph—CH₂— 4-SOCH3—Ph 270 4-F—Ph—CH₂—4-SO2CH3—Ph 271 4-F—Ph—CH₂— 4-OH—Ph 272 4-F—Ph—CH₂— 4-CH2OH—Ph 2734-F—Ph—CH₂— 4-CHOHCH3—Ph 274 4-F—Ph—CH₂— 4-COH(CH3)2—Ph 275 4-F—Ph—CH₂—4-CH3—Ph 276 4-F—Ph—CH₂— 4-C2H5—Ph 277 4-F—Ph—CH₂— 4-iPr—Ph 2784-F—Ph—CH₂— 4-tBu—Ph 279 4-F—Ph—CH₂— 4-Ph—Ph 280 4-F—Ph—CH₂— 4-CH2Ph—Ph281 4-F—Ph—CH₂— 4-CH2CO2Me—Ph 282 4-F—Ph—CH₂— 4-(1-piperidinyl)-Ph 2834-F—Ph—CH₂— 4-(1-pyrrolidinyl)-Ph 284 4-F—Ph—CH₂— 4-(2-imidazolyl)-Ph285 4-F—Ph—CH₂— 4-(1-imidazolyl)-Ph 286 4-F—Ph—CH₂— 4-(2-thiazolyl)-Ph287 4-F—Ph—CH₂— 4-(3-pyrazolyl)-Ph 288 4-F—Ph—CH₂— 4-(1-pyrazolyl)-Ph289 4-F—Ph—CH₂— 4-(1-tetrazolyl)-Ph 290 4-F—Ph—CH₂— 4-(5-tetrazolyl)-Ph291 4-F—Ph—CH₂— 4-(2-pyridyl)-Ph 292 4-F—Ph—CH₂— 4-(2-thienyl)-Ph 2934-F—Ph—CH₂— 4-(2-furanyl)-Ph 294 4-F—Ph—CH₂— 2-CN—Ph 295 4-F—Ph—CH₂—2-COCH3—Ph 296 4-F—Ph—CH₂— 2-CO2Me—Ph 297 4-F—Ph—CH₂— 2-CO2Et—Ph 2984-F—Ph—CH₂— 2-CO2H—Ph 299 4-F—Ph—CH₂— 2-CONH2—Ph 300 4-F—Ph—CH₂—2-CONHMe—Ph 301 4-F—Ph—CH₂— 2-F—Ph 302 4-F—Ph—CH₂— 2-Cl—Ph 3034-F—Ph—CH₂— 2-Br—Ph 304 4-F—Ph—CH₂— 2-NO2—Ph 305 4-F—Ph—CH₂— 2-NH2—Ph306 4-F—Ph—CH₂— 2-NHMe—Ph 307 4-F—Ph—CH₂— 2-NMe2—Ph 308 4-F—Ph—CH₂—2-NHCOCH3—Ph 309 4-F—Ph—CH₂— 2-SO2NH2—Ph 310 4-F—Ph—CH₂— 2-SO2NHMe—Ph311 4-F—Ph—CH₂— 2-CF3—Ph 312 4-F—Ph—CH₂— 2-OCH3—Ph 313 4-F—Ph—CH₂—2-OPh—Ph 314 4-F—Ph—CH₂— 2-OCF3—Ph 315 4-F—Ph—CH₂— 2-SCH3—Ph 3164-F—Ph—CH₂— 2-SOCH3—Ph 317 4-F—Ph—CH₂— 2-SO2CH3—Ph 318 4-F—Ph—CH₂—2-OH—Ph 319 4-F—Ph—CH₂— 2-CH2OH—Ph 320 4-F—Ph—CH₂— 2-CHOHCH3—Ph 3214-F—Ph—CH₂— 2-COH(CH3)2—Ph 322 4-F—Ph—CH₂— 2-CHOHPh—Ph 323 4-F—Ph—CH₂—2-CH3—Ph 324 4-F—Ph—CH₂— 2-C2H5—Ph 325 4-F—Ph—CH₂— 2-iPr—Ph 3264-F—Ph—CH₂— 2-tBu—Ph 327 4-F—Ph—CH₂— 2-Ph—Ph 328 4-F—Ph—CH₂— 2-CH2Ph—Ph329 4-F—Ph—CH₂— 2-CH2CO2Me—Ph 330 4-F—Ph—CH₂— 2-(1-piperidinyl)-Ph 3314-F—Ph—CH₂— 2-(1-pyrrolidinyl)-Ph 332 4-F—Ph—CH₂— 2-(2-imidazolyl)-Ph333 4-F—Ph—CH₂— 2-(1-imidazolyl)-Ph 334 4-F—Ph—CH₂— 2-(2-thiazolyl)-Ph335 4-F—Ph—CH₂— 2-(3-pyrazolyl)-Ph 336 4-F—Ph—CH₂— 2-(1-pyrazolyl)-Ph337 4-F—Ph—CH₂— 2-(1-tetrazolyl)-Ph 338 4-F—Ph—CH₂— 2-(5-tetrazolyl)-Ph339 4-F—Ph—CH₂— 2-(2-pyridyl)-Ph 340 4-F—Ph—CH₂— 2-(2-thienyl)-Ph 3414-F—Ph—CH₂— 2-(2-furanyl)-Ph 342 4-F—Ph—CH₂— 2,4-diF—Ph 343 4-F—Ph—CH₂—2,5-diF—Ph 344 4-F—Ph—CH₂— 2,6-diF—Ph 345 4-F—Ph—CH₂— 3,4-diF—Ph 3464-F—Ph—CH₂— 3,5-diF—Ph 347 4-F—Ph—CH₂— 2,4-diCl—Ph 348 4-F—Ph—CH₂—2,5-diCl—Ph 349 4-F—Ph—CH₂— 2,6-diCl—Ph 350 4-F—Ph—CH₂— 3,4-diCl—Ph 3514-F—Ph—CH₂— 3,5-diCl—Ph 352 4-F—Ph—CH₂— 3,4-diCF3—Ph 353 4-F—Ph—CH₂—3,5-diCF3—Ph 354 4-F—Ph—CH₂— 5-Cl-2-MeO—Ph 355 4-F—Ph—CH₂— 5-Cl-2-Me—Ph356 4-F—Ph—CH₂— 2-F-5-Me—Ph 357 4-F—Ph—CH₂— 2-F-5-NO2—Ph 358 4-F—Ph—CH₂—3,4-OCH2O—Ph 359 4-F—Ph—CH₂— 3,4-OCH2CH2O—Ph 360 4-F—Ph—CH₂—2-MeO-4-Me—Ph 361 4-F—Ph—CH₂— 2-MeO-5-Me—Ph 362 4-F—Ph—CH₂— 1-naphthyl363 4-F—Ph—CH₂— 2-naphthyl 364 4-F—Ph—CH₂— 2-thienyl 365 4-F—Ph—CH₂—3-thienyl 366 4-F—Ph—CH₂— 2-furanyl 367 4-F—Ph—CH₂— 3-furanyl 3684-F—Ph—CH₂— 2-pyridyl 369 4-F—Ph—CH₂— 3-pyridyl 370 4-F—Ph—CH₂—4-pyridyl 371 4-F—Ph—CH₂— 2-indolyl 372 4-F—Ph—CH₂— 3-indolyl 3734-F—Ph—CH₂— 5-indolyl 374 4-F—Ph—CH₂— 6-indolyl 375 4-F—Ph—CH₂—3-indazolyl 376 4-F—Ph—CH₂— 5-indazolyl 377 4-F—Ph—CH₂— 6-indazolyl 3784-F—Ph—CH₂— 2-imidazolyl 379 4-F—Ph—CH₂— 3-pyrazolyl 380 4-F—Ph—CH₂—2-thiazolyl 381 4-F—Ph—CH₂— 5-tetrazolyl 382 4-F—Ph—CH₂—2-benzimidazolyl 383 4-F—Ph—CH₂— 5-benzimidazolyl 384 4-F—Ph—CH₂—2-benzothiazolyl 385 4-F—Ph—CH₂— 5-benzothiazolyl 386 4-F—Ph—CH₂—2-benzoxazolyl 387 4-F—Ph—CH₂— 5-benzoxazolyl 388 4-F—Ph—CH₂—1-adamantyl 389 4-F—Ph—CH₂— 2-adamantyl 390 4-F—Ph—CH₂— t-Bu 3912-F—Ph—CH₂— 3-CN—Ph 392 2-F—Ph—CH₂— 3-COCH3—Ph 393 2-F—Ph—CH₂—3-CO2Me—Ph 394 2-F—Ph—CH₂— 3-CO2Et—Ph 395 2-F—Ph—CH₂— 3-CO2H—Ph 3962-F—Ph—CH₂— 3-CONH2—Ph 397 2-F—Ph—CH₂— 3-F—Ph 398 2-F—Ph—CH₂— 3-Cl—Ph399 2-F—Ph—CH₂— 3-NH2—Ph 400 2-F—Ph—CH₂— 3-SO2NH2—Ph 401 2-F—Ph—CH₂—3-CF3—Ph 402 2-F—Ph—CH₂— 3-OCH3—Ph 403 2-F—Ph—CH₂— 3-OEt—Ph 4042-F—Ph—CH₂— 3-OCF3—Ph 405 2-F—Ph—CH₂— 3-SO2CH3—Ph 406 2-F—Ph—CH₂—3-OH—Ph 407 2-F—Ph—CH₂— 3-CH3—Ph 408 2-F—Ph—CH₂— 3-C2H5—Ph 4092-F—Ph—CH₂— 4-CN—Ph 410 2-F—Ph—CH₂— 4-COCH3—Ph 411 2-F—Ph—CH₂—4-CO2Me—Ph 412 2-F—Ph—CH₂— 4-CO2Et—Ph 413 2-F—Ph—CH₂— 4-CO2H—Ph 4142-F—Ph—CH₂— 4-CONH2—Ph 415 2-F—Ph—CH₂— 4-F—Ph 416 2-F—Ph—CH₂— 4-Cl—Ph417 2-F—Ph—CH₂— 4-NH2—Ph 418 2-F—Ph—CH₂— 4-SO2NH2—Ph 419 2-F—Ph—CH₂—4-CF3—Ph 420 2-F—Ph—CH₂— 4-OCH3—Ph 421 2-F—Ph—CH₂— 4-OEt—Ph 4222-F—Ph—CH₂— 4-OCF3—Ph 423 2-F—Ph—CH₂— 4-SO2CH3—Ph 424 2-F—Ph—CH₂—4-OH—Ph 425 2-F—Ph—CH₂— 4-CH3—Ph 426 2-F—Ph—CH₂— 4-C2H5—Ph 4272-F—Ph—CH₂— 2,4-diF—Ph 428 2-F—Ph—CH₂— 2,5-diF—Ph 429 2-F—Ph—CH₂—3,4-diF—Ph 430 2-F—Ph—CH₂— 3,5-diF—Ph 431 2-F—Ph—CH₂— 2,4-diCl—Ph 4322-F—Ph—CH₂— 2,5-diCl—Ph 433 2-F—Ph—CH₂— 3,4-diCl—Ph 434 2-F—Ph—CH₂—3,5-diCl—Ph 435 2-F—Ph—CH₂— 3,4-OCH2O—Ph 436 2-F—Ph—CH₂— 3,4-OCH2CH2O—Ph437 2-F—Ph—CH₂— 2-thienyl 438 2-F—Ph—CH₂— 2-furanyl 439 2-F—Ph—CH₂—2-pyridyl 440 2-F—Ph—CH₂— 4-pyridyl 441 2-F—Ph—CH₂— 2-imidazolyl 4422-F—Ph—CH₂— 3-pyrazolyl 443 2-F—Ph—CH₂— 2-thiazolyl 444 2-F—Ph—CH₂—5-tetrazolyl 445 2-F—Ph—CH₂— 1-adamantyl 446 2,4-diF—Ph—CH₂— 3-CN—Ph 4472,4-diF—Ph—CH₂— 3-COCH3—Ph 448 2,4-diF—Ph—CH₂— 3-CO2Me—Ph 4492,4-diF—Ph—CH₂— 3-CO2Et—Ph 450 2,4-diF—Ph—CH₂— 3-CO2H—Ph 4512,4-diF—Ph—CH₂— 3-CONH2—Ph 452 2,4-diF—Ph—CH₂— 3-F—Ph 4532,4-diF—Ph—CH₂— 3-Cl—Ph 454 2,4-diF—Ph—CH₂— 3-NH2—Ph 455 2,4-diF—Ph—CH₂—3-SO2NH2—Ph 456 2,4-diF—Ph—CH₂— 3-CF3—Ph 457 2,4-diF—Ph—CH₂— 3-OCH3—Ph458 2,4-diF—Ph—CH₂— 3-OEt—Ph 459 2,4-diF—Ph—CH₂— 3-OCF3—Ph 4602,4-diF—Ph—CH₂— 3-SO2CH3—Ph 461 2,4-diF—Ph—CH₂— 3-OH—Ph 4622,4-diF—Ph—CH₂— 3-CH3—Ph 463 2,4-diF—Ph—CH₂— 3-C2H5—Ph 4642,4-diF—Ph—CH₂— 4-CN—Ph 465 2,4-diF—Ph—CH₂— 4-COCH3—Ph 4662,4-diF—Ph—CH₂— 4-CO2Me—Ph 467 2,4-diF—Ph—CH₂— 4-CO2Et—Ph 4682,4-diF—Ph—CH₂— 4-CO2H—Ph 469 2,4-diF—Ph—CH₂— 4-CONH2—Ph 4702,4-diF—Ph—CH₂— 4-F—Ph 471 2,4-diF—Ph—CH₂— 4-Cl—Ph 472 2,4-diF—Ph—CH₂—4-NH2—Ph 473 2,4-diF—Ph—CH₂— 4-SO2NH2—Ph 474 2,4-diF—Ph—CH₂— 4-CF3—Ph475 2,4-diF—Ph—CH₂— 4-OCH3—Ph 476 2,4-diF—Ph—CH₂— 4-OEt—Ph 4772,4-diF—Ph—CH₂— 4-OCF3—Ph 478 2,4-diF—Ph—CH₂— 4-SO2CH3—Ph 4792,4-diF—Ph—CH₂— 4-OH—Ph 480 2,4-diF—Ph—CH₂— 4-CH3—Ph 481 2,4-diF—Ph—CH₂—4-C2H5—Ph 482 2,4-diF—Ph—CH₂— 2,4-diF—Ph 483 2,4-diF—Ph—CH₂— 2,5-diF—Ph484 2,4-diF—Ph—CH₂— 3,4-diF—Ph 485 2,4-diF—Ph—CH₂— 3,5-diF—Ph 4862,4-diF—Ph—CH₂— 2,4-diCl—Ph 487 2,4-diF—Ph—CH₂— 2,5-diCl—Ph 4882,4-diF—Ph—CH₂— 3,4-diCl—Ph 489 2,4-diF—Ph—CH₂— 3,5-diCl—Ph 4902,4-diF—Ph—CH₂— 3,4-OCH2O—Ph 491 2,4-diF—Ph—CH₂— 3,4-OCH2CH2O—Ph 4922,4-diF—Ph—CH₂— 2-thienyl 493 2,4-diF—Ph—CH₂— 2-furanyl 4942,4-diF—Ph—CH₂— 2-pyridyl 495 2,4-diF—Ph—CH₂— 4-pyridyl 4962,4-diF—Ph—CH₂— 2-imidazolyl 497 2,4-diF—Ph—CH₂— 3-pyrazolyl 4982,4-diF—Ph—CH₂— 2-thiazolyl 499 2,4-diF—Ph—CH₂— 5-tetrazolyl 5002,4-diF—Ph—CH₂— 1-adamantyl 501 4-Cl—Ph—CH₂— Ph 502 4-Cl—Ph—CH₂— 3-CN—Ph503 4-Cl—Ph—CH₂— 3-COCH3—Ph 504 4-Cl—Ph—CH₂— 3-CO2Me—Ph 505 4-Cl—Ph—CH₂—3-CO2Et—Ph 506 4-Cl—Ph—CH₂— 3-CO2H—Ph 507 4-Cl—Ph—CH₂— 3-CONH2—Ph 5084-Cl—Ph—CH₂— 3-CONHMe—Ph 509 4-Cl—Ph—CH₂— 3-F—Ph 510 4-Cl—Ph—CH₂—3-Cl—Ph 511 4-Cl—Ph—CH₂— 3-Br—Ph 512 4-Cl—Ph—CH₂— 3-NO2—Ph 5134-Cl—Ph—CH₂— 3-NH2—Ph 514 4-Cl—Ph—CH₂— 3-NHMe—Ph 515 4-Cl—Ph—CH₂—3-NMe2—Ph 516 4-Cl—Ph—CH₂— 3-NHCOCH3—Ph 517 4-Cl—Ph—CH₂— 3-SO2NH2—Ph 5184-Cl—Ph—CH₂— 3-SO2NHMe—Ph 519 4-Cl—Ph—CH₂— 3-CF3—Ph 520 4-Cl—Ph—CH₂—3-OCH3—Ph 521 4-Cl—Ph—CH₂— 3-OPh—Ph 522 4-Cl—Ph—CH₂— 3-OCF3—Ph 5234-Cl—Ph—CH₂— 3-SCH3—Ph 524 4-Cl—Ph—CH₂— 3-SOCH3—Ph 525 4-Cl—Ph—CH₂—3-SO2CH3—Ph 526 4-Cl—Ph—CH₂— 3-OH—Ph 527 4-Cl—Ph—CH₂— 3-CH2OH—Ph 5284-Cl—Ph—CH₂— 3-CHOHCH3—Ph 529 4-Cl—Ph—CH₂— 3-COH(CH3)2—Ph 5304-Cl—Ph—CH₂— 3-CHOHPh—Ph 531 4-Cl—Ph—CH₂— 3-CH3—Ph 532 4-Cl—Ph—CH₂—3-C2H5—Ph 533 4-Cl—Ph—CH₂— 3-iPr—Ph 534 4-Cl—Ph—CH₂— 3-tBu—Ph 5354-Cl—Ph—CH₂— 3-Ph—Ph 536 4-Cl—Ph—CH₂— 3-CH2Ph—Ph 537 4-Cl—Ph—CH₂—3-CH2CO2Me—Ph 538 4-Cl—Ph—CH₂— 3-(1-piperidinyl)-Ph 539 4-Cl—Ph—CH₂—3-(1-pyrrolidinyl)-Ph 540 4-Cl—Ph—CH₂— 3-(2-imidazolyl)-Ph 5414-Cl—Ph—CH₂— 3-(1-imidazolyl)-Ph 542 4-Cl—Ph—CH₂— 3-(2-thiazolyl)-Ph 5434-Cl—Ph—CH₂— 3-(3-pyrazolyl)-Ph 544 4-Cl—Ph—CH₂— 3-(1-pyrazolyl)-Ph 5454-Cl—Ph—CH₂— 3-(1-tetrazolyl)-Ph 546 4-Cl—Ph—CH₂— 3-(5-tetrazolyl)-Ph547 4-Cl—Ph—CH₂— 3-(2-pyridyl)-Ph 548 4-Cl—Ph—CH₂— 3-(2-thienyl)-Ph 5494-Cl—Ph—CH₂— 3-(2-furanyl)-Ph 550 4-Cl—Ph—CH₂— 4-CN—Ph 551 4-Cl—Ph—CH₂—4-COCH3—Ph 552 4-Cl—Ph—CH₂— 4-CO2Me—Ph 553 4-Cl—Ph—CH₂— 4-CO2Et—Ph 5544-Cl—Ph—CH₂— 4-CO2H—Ph 555 4-Cl—Ph—CH₂— 4-CONH2—Ph 556 4-Cl—Ph—CH₂—4-CONHMe—Ph 557 4-Cl—Ph—CH₂— 4-CONHPh—Ph 558 4-Cl—Ph—CH₂— 4-NHCONH2—Ph559 4-Cl—Ph—CH₂— 4-F—Ph 560 4-Cl—Ph—CH₂— 4-Cl—Ph 561 4-Cl—Ph—CH₂—4-Br—Ph 562 4-Cl—Ph—CH₂— 4-NO2—Ph 563 4-Cl—Ph—CH₂— 4-NH2—Ph 5644-Cl—Ph—CH₂— 4-NHMe—Ph 565 4-Cl—Ph—CH₂— 4-NMe2—Ph 566 4-Cl—Ph—CH₂—4-NHCOCH3—Ph 567 4-Cl—Ph—CH₂— 4-SO2NH2—Ph 568 4-Cl—Ph—CH₂— 4-SO2NHMe—Ph569 4-Cl—Ph—CH₂— 4-CF3—Ph 570 4-Cl—Ph—CH₂— 4-OCH3—Ph 571 4-Cl—Ph—CH₂—4-OPh—Ph 572 4-Cl—Ph—CH₂— 4-OCF3—Ph 573 4-Cl—Ph—CH₂— 4-SCH3—Ph 5744-Cl—Ph—CH₂— 4-SOCH3—Ph 575 4-Cl—Ph—CH₂— 4-SO2CH3—Ph 576 4-Cl—Ph—CH₂—4-OH—Ph 577 4-Cl—Ph—CH₂— 4-CH2OH—Ph 578 4-Cl—Ph—CH₂— 4-CHOHCH3—Ph 5794-Cl—Ph—CH₂— 4-COH(CH3)2—Ph 580 4-Cl—Ph—CH₂— 4-CH3—Ph 581 4-Cl—Ph—CH₂—4-C2H5—Ph 582 4-Cl—Ph—CH₂— 4-iPr—Ph 583 4-Cl—Ph—CH₂— 4-tBu—Ph 5844-Cl—Ph—CH₂— 4-Ph—Ph 585 4-Cl—Ph—CH₂— 4-CH2Ph—Ph 586 4-Cl—Ph—CH₂—4-CH2CO2Me—Ph 587 4-Cl—Ph—CH₂— 4-(1-piperidinyl)-Ph 588 4-Cl—Ph—CH₂—4-(1-pyrrolidinyl)-Ph 589 4-Cl—Ph—CH₂— 4-(2-imidazolyl)-Ph 5904-Cl—Ph—CH₂— 4-(1-imidazolyl)-Ph 591 4-Cl—Ph—CH₂— 4-(2-thiazolyl)-Ph 5924-Cl—Ph—CH₂— 4-(3-pyrazolyl)-Ph 593 4-Cl—Ph—CH₂— 4-(1-pyrazolyl)-Ph 5944-Cl—Ph—CH₂— 4-(1-tetrazolyl)-Ph 595 4-Cl—Ph—CH₂— 4-(5-tetrazolyl)-Ph596 4-Cl—Ph—CH₂— 4-(2-pyridyl)-Ph 597 4-Cl—Ph—CH₂— 4-(2-thienyl)-Ph 5984-Cl—Ph—CH₂— 4-(2-furanyl)-Ph 599 4-Cl—Ph—CH₂— 2-CN—Ph 600 4-Cl—Ph—CH₂—2-COCH3—Ph 601 4-Cl—Ph—CH₂— 2-CO2Me—Ph 602 4-Cl—Ph—CH₂— 2-CO2Et—Ph 6034-Cl—Ph—CH₂— 2-CO2H—Ph 604 4-Cl—Ph—CH₂— 2-CONH2—Ph 605 4-Cl—Ph—CH₂—2-CONHMe—Ph 606 4-Cl—Ph—CH₂— 2-F—Ph 607 4-Cl—Ph—CH₂— 2-Cl—Ph 6084-Cl—Ph—CH₂— 2-Br—Ph 609 4-Cl—Ph—CH₂— 2-NO2—Ph 610 4-Cl—Ph—CH₂— 2-NH2—Ph611 4-Cl—Ph—CH₂— 2-NHMe—Ph 612 4-Cl—Ph—CH₂— 2-NMe2—Ph 613 4-Cl—Ph—CH₂—2-NHCOCH3—Ph 614 4-Cl—Ph—CH₂— 2-SO2NH2—Ph 615 4-Cl—Ph—CH₂— 2-SO2NHMe—Ph616 4-Cl—Ph—CH₂— 2-CF3—Ph 617 4-Cl—Ph—CH₂— 2-OCH3—Ph 618 4-Cl—Ph—CH₂—2-OPh—Ph 619 4-Cl—Ph—CH₂— 2-OCF3—Ph 620 4-Cl—Ph—CH₂— 2-SCH3—Ph 6214-Cl—Ph—CH₂— 2-SOCH3—Ph 622 4-Cl—Ph—CH₂— 2-SO2CH3—Ph 623 4-Cl—Ph—CH₂—2-OH—Ph 624 4-Cl—Ph—CH₂— 2-CH2OH—Ph 625 4-Cl—Ph—CH₂— 2-CHOHCH3—Ph 6264-Cl—Ph—CH₂— 2-COH(CH3)2—Ph 627 4-Cl—Ph—CH₂— 2-CHOHPh—Ph 6284-Cl—Ph—CH₂— 2-CH3—Ph 629 4-Cl—Ph—CH₂— 2-C2H5—Ph 630 4-Cl—Ph—CH₂—2-iPr—Ph 631 4-Cl—Ph—CH₂— 2-tBu—Ph 632 4-Cl—Ph—CH₂— 2-Ph—Ph 6334-Cl—Ph—CH₂— 2-CH2Ph—Ph 634 4-Cl—Ph—CH₂— 2-CH2CO2Me—Ph 635 4-Cl—Ph—CH₂—2-(1-piperidinyl)-Ph 636 4-Cl—Ph—CH₂— 2-(1-pyrrolidinyl)-Ph 6374-Cl—Ph—CH₂— 2-(2-imidazolyl)-Ph 638 4-Cl—Ph—CH₂— 2-(1-imidazolyl)-Ph639 4-Cl—Ph—CH₂— 2-(2-thiazolyl)-Ph 640 4-Cl—Ph—CH₂— 2-(3-pyrazolyl)-Ph641 4-Cl—Ph—CH₂— 2-(1-pyrazolyl)-Ph 642 4-Cl—Ph—CH₂— 2-(1-tetrazolyl)-Ph643 4-Cl—Ph—CH₂— 2-(5-tetrazolyl)-Ph 644 4-Cl—Ph—CH₂— 2-(2-pyridyl)-Ph645 4-Cl—Ph—CH₂— 2-(2-thienyl)-Ph 646 4-Cl—Ph—CH₂— 2-(2-furanyl)-Ph 6474-Cl—Ph—CH₂— 2,4-diF—Ph 648 4-Cl—Ph—CH₂— 2,5-diF—Ph 649 4-Cl—Ph—CH₂—2,6-diF—Ph 650 4-Cl—Ph—CH₂— 3,4-diF—Ph 651 4-Cl—Ph—CH₂— 3,5-diF—Ph 6524-Cl—Ph—CH₂— 2,4-diCl—Ph 653 4-Cl—Ph—CH₂— 2,5-diCl—Ph 654 4-Cl—Ph—CH₂—2,6-diCl—Ph 655 4-Cl—Ph—CH₂— 3,4-diCl—Ph 656 4-Cl—Ph—CH₂— 3,5-diCl—Ph657 4-Cl—Ph—CH₂— 3,4-diCF3—Ph 658 4-Cl—Ph—CH₂— 3,5-diCF3—Ph 6594-Cl—Ph—CH₂— 5-Cl-2-MeO—Ph 660 4-Cl—Ph—CH₂— 5-Cl-2-Me—Ph 6614-Cl—Ph—CH₂— 2-F-5-Me—Ph 662 4-Cl—Ph—CH₂— 2-F-5-NO2—Ph 663 4-Cl—Ph—CH₂—3,4-OCH2O—Ph 664 4-Cl—Ph—CH₂— 3,4-OCH2CH2O—Ph 665 4-Cl—Ph—CH₂—2-MeO-4-Me—Ph 666 4-Cl—Ph—CH₂— 2-MeO-5-Me—Ph 667 4-Cl—Ph—CH₂— 1-naphthyl668 4-Cl—Ph—CH₂— 2-naphthyl 669 4-Cl—Ph—CH₂— 2-thienyl 670 4-Cl—Ph—CH₂—3-thienyl 671 4-Cl—Ph—CH₂— 2-furanyl 672 4-Cl—Ph—CH₂— 3-furanyl 6734-Cl—Ph—CH₂— 2-pyridyl 674 4-Cl—Ph—CH₂— 3-pyridyl 675 4-Cl—Ph—CH₂—4-pyridyl 676 4-Cl—Ph—CH₂— 2-indolyl 677 4-Cl—Ph—CH₂— 3-indolyl 6784-Cl—Ph—CH₂— 5-indolyl 679 4-Cl—Ph—CH₂— 6-indolyl 680 4-Cl—Ph—CH₂—3-indazolyl 681 4-Cl—Ph—CH₂— 5-indazolyl 682 4-Cl—Ph—CH₂— 6-indazolyl683 4-Cl—Ph—CH₂— 2-imidazolyl 684 4-Cl—Ph—CH₂— 3-pyrazolyl 6854-Cl—Ph—CH₂— 2-thiazolyl 686 4-Cl—Ph—CH₂— 5-tetrazolyl 687 4-Cl—Ph—CH₂—2-benzimidazolyl 688 4-Cl—Ph—CH₂— 5-benzimidazolyl 689 4-Cl—Ph—CH₂—2-benzothiazolyl 690 4-Cl—Ph—CH₂— 5-benzothiazolyl 691 4-Cl—Ph—CH₂—2-benzoxazolyl 692 4-Cl—Ph—CH₂— 5-benzoxazolyl 693 4-Cl—Ph—CH₂—1-adamantyl 694 4-Cl—Ph—CH₂— 2-adamantyl 695 4-Cl—Ph—CH₂— t-Bu 6962-Cl—Ph—CH₂— 3-CN—Ph 697 2-Cl—Ph—CH₂— 3-COCH3—Ph 698 2-Cl—Ph—CH₂—3-CO2Me—Ph 699 2-Cl—Ph—CH₂— 3-CO2Et—Ph 700 2-Cl—Ph—CH₂— 3-CO2H—Ph 7012-Cl—Ph—CH₂— 3-CONH2—Ph 702 2-Cl—Ph—CH₂— 3-F—Ph 703 2-Cl—Ph—CH₂— 3-Cl—Ph704 2-Cl—Ph—CH₂— 3-NH2—Ph 705 2-Cl—Ph—CH₂— 3-SO2NH2—Ph 706 2-Cl—Ph—CH₂—3-CF3—Ph 707 2-Cl—Ph—CH₂— 3-OCH3—Ph 708 2-Cl—Ph—CH₂— 3-OEt—Ph 7092-Cl—Ph—CH₂— 3-OCF3—Ph 710 2-Cl—Ph—CH₂— 3-SO2CH3—Ph 711 2-Cl—Ph—CH₂—3-OH—Ph 712 2-Cl—Ph—CH₂— 3-CH3—Ph 713 2-Cl—Ph—CH₂— 3-C2H5—Ph 7142-Cl—Ph—CH₂— 4-CN—Ph 715 2-Cl—Ph—CH₂— 4-COCH3—Ph 716 2-Cl—Ph—CH₂—4-CO2Me—Ph 717 2-Cl—Ph—CH₂— 4-CO2Et—Ph 718 2-Cl—Ph—CH₂— 4-CO2H—Ph 7192-Cl—Ph—CH₂— 4-CONH2—Ph 720 2-Cl—Ph—CH₂— 4-F—Ph 721 2-Cl—Ph—CH₂— 4-Cl—Ph722 2-Cl—Ph—CH₂— 4-NH2—Ph 723 2-Cl—Ph—CH₂— 4-SO2NH2—Ph 724 2-Cl—Ph—CH₂—4-CF3—Ph 725 2-Cl—Ph—CH₂— 4-OCH3—Ph 726 2-Cl—Ph—CH₂— 4-OEt—Ph 7272-Cl—Ph—CH₂— 4-OCF3—Ph 728 2-Cl—Ph—CH₂— 4-SO2CH3—Ph 729 2-Cl—Ph—CH₂—4-OH—Ph 730 2-Cl—Ph—CH₂— 4-CH3—Ph 731 2-Cl—Ph—CH₂— 4-C2H5—Ph 7322-Cl—Ph—CH₂— 2,4-diF—Ph 733 2-Cl—Ph—CH₂— 2,5-diF—Ph 734 2-Cl—Ph—CH₂—3,4-diF—Ph 735 2-Cl—Ph—CH₂— 3,5-diF—Ph 736 2-Cl—Ph—CH₂— 2,4-diCl—Ph 7372-Cl—Ph—CH₂— 2,5-diCl—Ph 738 2-Cl—Ph—CH₂— 3,4-diCl—Ph 739 2-Cl—Ph—CH₂—3,5-diCl—Ph 740 2-Cl—Ph—CH₂— 3,4-OCH2O—Ph 741 2-Cl—Ph—CH₂—3,4-OCH2CH2O—Ph 742 2-Cl—Ph—CH₂— 2-thienyl 743 2-Cl—Ph—CH₂— 2-furanyl744 2-Cl—Ph—CH₂— 2-pyridyl 745 2-Cl—Ph—CH₂— 4-pyridyl 746 2-Cl—Ph—CH₂—2-imidazolyl 747 2-Cl—Ph—CH₂— 3-pyrazolyl 748 2-Cl—Ph—CH₂— 2-thiazolyl749 2-Cl—Ph—CH₂— 5-tetrazolyl 750 2-Cl—Ph—CH₂— 1-adamantyl 7512,4-diCl—Ph—CH₂— 3-CN—Ph 752 2,4-diCl—Ph—CH₂— 3-COCH3—Ph 7532,4-diCl—Ph—CH₂— 3-CO2Me—Ph 754 2,4-diCl—Ph—CH₂— 3-CO2Et—Ph 7552,4-diCl—Ph—CH₂— 3-CO2H—Ph 756 2,4-diCl—Ph—CH₂— 3-CONH2—Ph 7572,4-diCl—Ph—CH₂— 3-F—Ph 758 2,4-diCl—Ph—CH₂— 3-Cl—Ph 7592,4-diCl—Ph—CH₂— 3-NH2—Ph 760 2,4-diCl—Ph—CH₂— 3-SO2NH2—Ph 7612,4-diCl—Ph—CH₂— 3-CF3—Ph 762 2,4-diCl—Ph—CH₂— 3-OCH3—Ph 7632,4-diCl—Ph—CH₂— 3-OEt—Ph 764 2,4-diCl—Ph—CH₂— 3-OCF3—Ph 7652,4-diCl—Ph—CH₂— 3-SO2CH3—Ph 766 2,4-diCl—Ph—CH₂— 3-OH—Ph 7672,4-diCl—Ph—CH₂— 3-CH3—Ph 768 2,4-diCl—Ph—CH₂— 3-C2H5—Ph 7692,4-diCl—Ph—CH₂— 4-CN—Ph 770 2,4-diCl—Ph—CH₂— 4-COCH3—Ph 7712,4-diCl—Ph—CH₂— 4-CO2Me—Ph 772 2,4-diCl—Ph—CH₂— 4-CO2Et—Ph 7732,4-diCl—Ph—CH₂— 4-CO2H—Ph 774 2,4-diCl—Ph—CH₂— 4-CONH2—Ph 7752,4-diCl—Ph—CH₂— 4-F—Ph 776 2,4-diCl—Ph—CH₂— 4-Cl—Ph 7772,4-diCl—Ph—CH₂— 4-NH2—Ph 778 2,4-diCl—Ph—CH₂— 4-SO2NH2—Ph 7792,4-diCl—Ph—CH₂— 4-CF3—Ph 780 2,4-diCl—Ph—CH₂— 4-OCH3—Ph 7812,4-diCl—Ph—CH₂— 4-OEt—Ph 782 2,4-diCl—Ph—CH₂— 4-OCF3—Ph 7832,4-diCl—Ph—CH₂— 4-SO2CH3—Ph 784 2,4-diCl—Ph—CH₂— 4-OH—Ph 7852,4-diCl—Ph—CH₂— 4-CH3—Ph 786 2,4-diCl—Ph—CH₂— 4-C2H5—Ph 7872,4-diCl—Ph—CH₂— 2,4-diF—Ph 788 2,4-diCl—Ph—CH₂— 2,5-diF—Ph 7892,4-diCl—Ph—CH₂— 3,4-diF—Ph 790 2,4-diCl—Ph—CH₂— 3,5-diF—Ph 7912,4-diCl—Ph—CH₂— 2,4-diCl—Ph 792 2,4-diCl—Ph—CH₂— 2,5-diCl—Ph 7932,4-diCl—Ph—CH₂— 3,4-diCl—Ph 794 2,4-diCl—Ph—CH₂— 3,5-diCl—Ph 7952,4-diCl—Ph—CH₂— 3,4-OCH2O—Ph 796 2,4-diCl—Ph—CH₂— 3,4-OCH2CH2O—Ph 7972,4-diCl—Ph—CH₂— 2-thienyl 798 2,4-diCl—Ph—CH₂— 2-furanyl 7992,4-diCl—Ph—CH₂— 2-pyridyl 800 2,4-diCl—Ph—CH₂— 4-pyridyl 8012,4-diCl—Ph—CH₂— 2-imidazolyl 802 2,4-diCl—Ph—CH₂— 3-pyrazolyl 8032,4-diCl—Ph—CH₂— 2-thiazolyl 804 2,4-diCl—Ph—CH₂— 5-tetrazolyl 8052,4-diCl—Ph—CH₂— 1-adamantyl 806 3-OCH3—Ph—CH₂— 3-CN—Ph 8073-OCH3—Ph—CH₂— 3-COCH3—Ph 808 3-OCH3—Ph—CH₂— 3-CO2Me—Ph 8093-OCH3—Ph—CH₂— 3-CO2Et—Ph 810 3-OCH3—Ph—CH₂— 3-CO2H—Ph 8113-OCH3—Ph—CH₂— 3-CONH2—Ph 812 3-OCH3—Ph—CH₂— 3-F—Ph 813 3-OCH3—Ph—CH₂—3-Cl—Ph 814 3-OCH3—Ph—CH₂— 3-NH2—Ph 815 3-OCH3—Ph—CH₂— 3-SO2NH2—Ph 8163-OCH3—Ph—CH₂— 3-CF3—Ph 817 3-OCH3—Ph—CH₂— 3-OCH3—Ph 818 3-OCH3—Ph—CH₂—3-OEt—Ph 819 3-OCH3—Ph—CH₂— 3-OCF3—Ph 820 3-OCH3—Ph—CH₂— 3-SO2CH3—Ph 8213-OCH3—Ph—CH₂— 3-OH—Ph 822 3-OCH3—Ph—CH₂— 3-CH3—Ph 823 3-OCH3—Ph—CH₂—3-C2H5—Ph 824 3-OCH3—Ph—CH₂— 4-CN—Ph 825 3-OCH3—Ph—CH₂— 4-COCH3—Ph 8263-OCH3—Ph—CH₂— 4-CO2Me—Ph 827 3-OCH3—Ph—CH₂— 4-CO2Et—Ph 8283-OCH3—Ph—CH₂— 4-CO2H—Ph 829 3-OCH3—Ph—CH₂— 4-CONH2—Ph 8303-OCH3—Ph—CH₂— 4-F—Ph 831 3-OCH3—Ph—CH₂— 4-Cl—Ph 832 3-OCH3—Ph—CH₂—4-NH2—Ph 833 3-OCH3—Ph—CH₂— 4-SO2NH2—Ph 834 3-OCH3—Ph—CH₂— 4-CF3—Ph 8353-OCH3—Ph—CH₂— 4-OCH3—Ph 836 3-OCH3—Ph—CH₂— 4-OEt—Ph 837 3-OCH3—Ph—CH₂—4-OCF3—Ph 838 3-OCH3—Ph—CH₂— 4-SO2CH3—Ph 839 3-OCH3—Ph—CH₂— 4-OH—Ph 8403-OCH3—Ph—CH₂— 4-CH3—Ph 841 3-OCH3—Ph—CH₂— 4-C2H5—Ph 842 3-OCH3—Ph—CH₂—2,4-diF—Ph 843 3-OCH3—Ph—CH₂— 2,5-diF—Ph 844 3-OCH3—Ph—CH₂— 3,4-diF—Ph845 3-OCH3—Ph—CH₂— 3,5-diF—Ph 846 3-OCH3—Ph—CH₂— 2,4-diCl—Ph 8473-OCH3—Ph—CH₂— 2,5-diCl—Ph 848 3-OCH3—Ph—CH₂— 3,4-diCl—Ph 8493-OCH3—Ph—CH₂— 3,5-diCl—Ph 850 3-OCH3—Ph—CH₂— 3,4-OCH2O—Ph 8513-OCH3—Ph—CH₂— 3,4-OCH2CH2O—Ph 852 3-OCH3—Ph—CH₂— 2-thienyl 8533-OCH3—Ph—CH₂— 2-furanyl 854 3-OCH3—Ph—CH₂— 2-pyridyl 855 3-OCH3—Ph—CH₂—4-pyridyl 856 3-OCH3—Ph—CH₂— 2-imidazolyl 857 3-OCH3—Ph—CH₂— 3-pyrazolyl858 3-OCH3—Ph—CH₂— 2-thiazolyl 859 3-OCH3—Ph—CH₂— 5-tetrazolyl 8603-OCH3—Ph—CH₂— 1-adamantyl 861 2-thienylmethyl 3-CN—Ph 8622-thienylmethyl 3-COCH3—Ph 863 2-thienylmethyl 3-F—Ph 8642-thienylmethyl 3-Cl—Ph 865 2-thienylmethyl 3-NH2—Ph 866 2-thienylmethyl3-OCH3—Ph 867 2-thienylmethyl 3-OH—Ph 868 2-thienylmethyl 4-CN—Ph 8692-thienylmethyl 4-COCH3—Ph 870 2-thienylmethyl 4-F—Ph 8712-thienylmethyl 4-Cl—Ph 872 2-thienylmethyl 4-NH2—Ph 873 2-thienylmethyl4-OCH3—Ph 874 2-thienylmethyl 4-OH—Ph 875 2-thienylmethyl 3,4-diF—Ph 8762-thienylmethyl 3,5-diF—Ph 877 2-thienylmethyl 3,4-diCl—Ph 8782-thienylmethyl 3,5-diCl—Ph 879 2-thienylmethyl 3,4-OCH2O—Ph 8802-thienylmethyl 3,4-OCH2CH2O—Ph 881 3-thienylmethyl 3-CN—Ph 8823-thienylmethyl 3-COCH3—Ph 883 3-thienylmethyl 3-F—Ph 8843-thienylmethyl 3-Cl—Ph 885 3-thienylmethyl 3-NH2—Ph 886 3-thienylmethyl3-OCH3—Ph 887 3-thienylmethyl 3-OH—Ph 888 3-thienylmethyl 4-CN—Ph 8893-thienylmethyl 4-COCH3—Ph 890 3-thienylmethyl 4-F—Ph 8913-thienylmethyl 4-Cl—Ph 892 3-thienylmethyl 4-NH2—Ph 893 3-thienylmethyl4-OCH3—Ph 894 3-thienylmethyl 4-OH—Ph 895 3-thienylmethyl 3,4-diF—Ph 8963-thienylmethyl 3,5-diF—Ph 897 3-thienylmethyl 3,4-diCl—Ph 8983-thienylmethyl 3,5-diCl—Ph 899 3-thienylmethyl 3,4-OCH2O—Ph 9003-thienylmethyl 3,4-OCH2CH2O—Ph 901 2-furanylmethyl 3-CN—Ph 9022-furanylmethyl 3-COCH3—Ph 903 2-furanylmethyl 3-F—Ph 9042-furanylmethyl 3-Cl—Ph 905 2-furanylmethyl 3-NH2—Ph 906 2-furanylmethyl3-OCH3—Ph 907 2-furanylmethyl 3-OH—Ph 908 2-furanylmethyl 4-CN—Ph 9092-furanylmethyl 4-COCH3—Ph 910 2-furanylmethyl 4-F—Ph 9112-furanylmethyl 4-Cl—Ph 912 2-furanylmethyl 4-NH2—Ph 913 2-furanylmethyl4-OCH3—Ph 914 2-furanylmethyl 4-OH—Ph 915 2-furanylmethyl 3,4-diF—Ph 9162-furanylmethyl 3,5-diF—Ph 917 2-furanylmethyl 3,4-diCl—Ph 9182-furanylmethyl 3,5-diCl—Ph 919 2-furanylmethyl 3,4-OCH2O—Ph 9202-furanylmethyl 3,4-OCH2CH2O—Ph 921 3-furanylmethyl 3-CN—Ph 9223-furanylmethyl 3-COCH3—Ph 923 3-furanylmethyl 3-F—Ph 9243-furanylmethyl 3-Cl—Ph 925 3-furanylmethyl 3-NH2—Ph 926 3-furanylmethyl3-OCH3—Ph 927 3-furanylmethyl 3-OH—Ph 928 3-furanylmethyl 4-CN—Ph 9293-furanylmethyl 4-COCH3—Ph 930 3-furanylmethyl 4-F—Ph 9313-furanylmethyl 4-Cl—Ph 932 3-furanylmethyl 4-NH2—Ph 933 3-furanylmethyl4-OCH3—Ph 934 3-furanylmethyl 4-OH—Ph 935 3-furanylmethyl 3,4-diF—Ph 9363-furanylmethyl 3,5-diF—Ph 937 3-furanylmethyl 3,4-diCl—Ph 9383-furanylmethyl 3,5-diCl—Ph 939 3-furanylmethyl 3,4-OCH2O—Ph 9403-furanylmethyl 3,4-OCH2CH2O—Ph 941 2-pyridylmethyl 3-CN—Ph 9422-pyridylmethyl 3-COCH3—Ph 943 2-pyridylmethyl 3-F—Ph 9442-pyridylmethyl 3-Cl—Ph 945 2-pyridylmethyl 3-NH2—Ph 946 2-pyridylmethyl3-OCH3—Ph 947 2-pyridylmethyl 3-OH—Ph 948 2-pyridylmethyl 4-CN—Ph 9492-pyridylmethyl 4-COCH3—Ph 950 2-pyridylmethyl 4-F—Ph 9512-pyridylmethyl 4-Cl—Ph 952 2-pyridylmethyl 4-NH2—Ph 953 2-pyridylmethyl4-OCH3—Ph 954 2-pyridylmethyl 4-OH—Ph 955 2-pyridylmethyl 3,4-diF—Ph 9562-pyridylmethyl 3,5-diF—Ph 957 2-pyridylmethyl 3,4-diCl—Ph 9582-pyridylmethyl 3,5-diCl—Ph 959 2-pyridylmethyl 3,4-OCH2O—Ph 9602-pyridylmethyl 3,4-OCH2CH2O—Ph 961 3-pyridylmethyl 3-CN—Ph 9623-pyridylmethyl 3-COCH3—Ph 963 3-pyridylmethyl 3-F—Ph 9643-pyridylmethyl 3-Cl—Ph 965 3-pyridylmethyl 3-NH2—Ph 966 3-pyridylmethyl3-OCH3—Ph 967 3-pyridylmethyl 3-OH—Ph 968 3-pyridylmethyl 4-CN—Ph 9693-pyridylmethyl 4-COCH3—Ph 970 3-pyridylmethyl 4-F—Ph 9713-pyridylmethyl 4-Cl—Ph 972 3-pyridylmethyl 4-NH2—Ph 973 3-pyridylmethyl4-OCH3—Ph 974 3-pyridylmethyl 4-OH—Ph 975 3-pyridylmethyl 3,4-diF—Ph 9763-pyridylmethyl 3,5-diF—Ph 977 3-pyridylmethyl 3,4-diCl—Ph 9783-pyridylmethyl 3,5-diCl—Ph 979 3-pyridylmethyl 3,4-OCH2O—Ph 9803-pyridylmethyl 3,4-OCH2CH2O—Ph 981 4-pyridylmethyl 3-CN—Ph 9824-pyridylmethyl 3-COCH3—Ph 983 4-pyridylmethyl 3-F—Ph 9844-pyridylmethyl 3-Cl—Ph 985 4-pyridylmethyl 3-NH2—Ph 986 4-pyridylmethyl3-OCH3—Ph 987 4-pyridylmethyl 3-OH—Ph 988 4-pyridylmethyl 4-CN—Ph 9894-pyridylmethyl 4-COCH3—Ph 990 4-pyridylmethyl 4-F—Ph 9914-pyridylmethyl 4-Cl—Ph 992 4-pyridylmethyl 4-NH2—Ph 993 4-pyridylmethyl4-OCH3—Ph 994 4-pyridylmethyl 4-OH—Ph 995 4-pyridylmethyl 3,4-diF—Ph 9964-pyridylmethyl 3,5-diF—Ph 997 4-pyridylmethyl 3,4-diCl—Ph 9984-pyridylmethyl 3,5-diCl—Ph 999 4-pyridylmethyl 3,4-OCH2O—Ph 10004-pyridylmethyl 3,4-OCH2CH2O—Ph 1001 3-indolylmethyl 3-CN—Ph 10023-indolylmethyl 3-COCH3—Ph 1003 3-indolylmethyl 3-F—Ph 10043-indolylmethyl 3-Cl—Ph 1005 3-indolylmethyl 3-NH2—Ph 10063-indolylmethyl 3-OCH3—Ph 1007 3-indolylmethyl 3-OH—Ph 10083-indolylmethyl 4-CN—Ph 1009 3-indolylmethyl 4-COCH3—Ph 10103-indolylmethyl 4-F—Ph 1011 3-indolylmethyl 4-Cl—Ph 1012 3-indolylmethyl4-NH2—Ph 1013 3-indolylmethyl 4-OCH3—Ph 1014 3-indolylmethyl 4-OH—Ph1015 3-indolylmethyl 3,4-diF—Ph 1016 3-indolylmethyl 3,5-diF—Ph 10173-indolylmethyl 3,4-diCl—Ph 1018 3-indolylmethyl 3,5-diCl—Ph 10193-indolylmethyl 3,4-OCH2O—Ph 1020 3-indolylmethyl 3,4-OCH2CH2O—Ph 10215-indolylmethyl 3-CN—Ph 1022 5-indolylmethyl 3-COCH3—Ph 10235-indolylmethyl 3-F—Ph 1024 5-indolylmethyl 3-Cl—Ph 1025 5-indolylmethyl3-NH2—Ph 1026 5-indolylmethyl 3-OCH3—Ph 1027 5-indolylmethyl 3-OH—Ph1028 5-indolylmethyl 4-CN—Ph 1029 5-indolylmethyl 4-COCH3—Ph 10305-indolylmethyl 4-F—Ph 1031 5-indolylmethyl 4-Cl—Ph 1032 5-indolylmethyl4-NH2—Ph 1033 5-indolylmethyl 4-OCH3—Ph 1034 5-indolylmethyl 4-OH—Ph1035 5-indolylmethyl 3,4-diF—Ph 1036 5-indolylmethyl 3,5-diF—Ph 10375-indolylmethyl 3,4-diCl—Ph 1038 5-indolylmethyl 3,5-diCl—Ph 10395-indolylmethyl 3,4-OCH2O—Ph 1040 5-indolylmethyl 3,4-OCH2CH2O—Ph 10415-indazolylmethyl 3-CN—Ph 1042 5-indazolylmethyl 3-COCH3—Ph 10435-indazolylmethyl 3-F—Ph 1044 5-indazolylmethyl 3-Cl—Ph 10455-indazolylmethyl 3-NH2—Ph 1046 5-indazolylmethyl 3-OCH3—Ph 10475-indazolylmethyl 3-OH—Ph 1048 5-indazolylmethyl 4-CN—Ph 10495-indazolylmethyl 4-COCH3—Ph 1050 5-indazolylmethyl 4-F—Ph 10515-indazolylmethyl 4-Cl—Ph 1052 5-indazolylmethyl 4-NH2—Ph 10535-indazolylmethyl 4-OCH3—Ph 1054 5-indazolylmethyl 4-OH—Ph 10555-indazolylmethyl 3,4-diF—Ph 1056 5-indazolylmethyl 3,5-diF—Ph 10575-indazolylmethyl 3,4-diCl—Ph 1058 5-indazolylmethyl 3,5-diCl—Ph 10595-indazolylmethyl 3,4-OCH2O—Ph 1060 5-indazolylmethyl 3,4-OCH2CH2O—Ph1061 5- 3-CN—Ph benzimidazolylmethyl 1062 5- 3-COCH3—Phbenzimidazolylmethyl 1063 5- 3-F—Ph benzimidazolylmethyl 1064 5- 3-Cl—Phbenzimidazolylmethyl 1065 5- 3-NH2—Ph benzimidazolylmethyl 1066 5-3-OCH3—Ph benzimidazolylmethyl 1067 5- 3-OH—Ph benzimidazolylmethyl 10685- 4-CN—Ph benzimidazolylmethyl 1069 5- 4-COCH3—Ph benzimidazolylmethyl1070 5- 4-F—Ph benzimidazolylmethyl 1071 5- 4-Cl—Ph benzimidazolylmethyl1072 5- 4-NH2—Ph benzimidazolylmethyl 1073 5- 4-OCH3—Phbenzimidazolylmethyl 1074 5- 4-OH—Ph benzimidazolylmethyl 1075 5-3,4-diF—Ph benzimidazolylmethyl 1076 5- 3,5-diF—Ph benzimidazolylmethyl1077 5- 3,4-diCl—Ph benzimidazolylmethyl 1078 5- 3,5-diCl—Phbenzimidazolylmethyl 1079 5- 3,4-OCH2O—Ph benzimidazolylmethyl 1080 5-3,4-OCH2CH2O—Ph benzimidazolylmethyl 1081 5- 3-CN—Phbenzothiazolylmethyl 1082 5- 3-COCH3—Ph benzothiazolylmethyl 1083 5-3-F—Ph benzothiazolylmethyl 1084 5- 3-Cl—Ph benzothiazolylmethyl 1085 5-3-NH2—Ph benzothiazolylmethyl 1086 5- 3-OCH3—Ph benzothiazolylmethyl1087 5- 3-OH—Ph benzothiazolylmethyl 1088 5- 4-CN—Phbenzothiazolylmethyl 1089 5- 4-COCH3—Ph benzothiazolylmethyl 1090 5-4-F—Ph benzothiazolylmethyl 1091 5- 4-Cl—Ph benzothiazolylmethyl 1092 5-4-NH2—Ph benzothiazolylmethyl 1093 5- 4-OCH3—Ph benzothiazolylmethyl1094 5- 4-OH—Ph benzothiazolylmethyl 1095 5- 3,4-diF—Phbenzothiazolylmethyl 1096 5- 3,5-diF—Ph benzothiazolylmethyl 1097 5-3,4-diCl—Ph benzothiazolylmethyl 1098 5- 3,5-diCl—Phbenzothiazolylmethyl 1099 5- 3,4-OCH2O—Ph benzothiazolylmethyl 1100 5-3,4-OCH2CH2O—Ph benzothiazolylmethyl 1101 5- 3-CN—Ph benzoxazolylmethyl1102 5- 3-COCH3—Ph benzoxazolylmethyl 1103 5- 3-F—Ph benzoxazolylmethyl1104 5- 3-Cl—Ph benzoxazolylmethyl 1105 5- 3-NH2—Ph benzoxazolylmethyl1106 5- 3-OCH3—Ph benzoxazolylmethyl 1107 5- 3-OH—Ph benzoxazolylmethyl1108 5- 4-CN—Ph benzoxazolylmethyl 1109 5- 4-COCH3—Ph benzoxazolylmethyl1110 5- 4-F—Ph benzoxazolylmethyl 1111 5- 4-Cl—Ph benzoxazolylmethyl1112 5- 4-NH2—Ph benzoxazolylmethyl 1113 5- 4-OCH3—Ph benzoxazolylmethyl1114 5- 4-OH—Ph benzoxazolylmethyl 1115 5- 3,4-diF—Ph benzoxazolylmethyl1116 5- 3,5-diF—Ph benzoxazolylmethyl 1117 5- 3,4-diCl—Phbenzoxazolylmethyl 1118 5- 3,5-diCl—Ph benzoxazolylmethyl 1119 5-3,4-OCH2O—Ph benzoxazolylmethyl 1120 5- 3,4-OCH2CH2O—Phbenzoxazolylmethyl *All stereocenters are (+/−) unless otherwiseindicated.

UTILITY

The utility of the compounds in accordance with the present invention asmodulators of chemokine receptor activity may be demonstrated bymethodology known in the art, such as the assays for CCR-2 and CCR-3ligand binding, as disclosed by Ponath et al., J. Exp. Med., 183,2437-2448 (1996) and Uguccioni et al., J. Clin. Invest., 100, 1137-1143(1997). Cell lines for expressing the receptor of interest include thosenaturally expressing the chemokine receptor, such as EOL-3 or THP-1,those induced to express the chemokine receptor by the addition ofchemical or protein agents, such as HL-60 or AML14.3D10 cells treatedwith, for example, butyric acid with interleukin-5 present, or a cellengineered to express a recombinant chemokine receptor, such as CHO orHEK-293. Finally, blood or tissue cells, for example human peripheralblood eosinophils, isolated using methods as described by Hansel et al.,J. Immunol. Methods, 145, 105-110 (1991), can be utilized in suchassays. In particular, the compound of the present invention haveactivity in binding to the CCR-3 receptor in the aforementioned assays.As used herein, “activity” is intended to mean a compound demonstratingan IC50 of 10 mM or lower in concentration when measured in theaforementioned assays. Such a result is indicative of the intrinsicactivity of the compounds as modulators of chemokine receptor activity.A general binding protocol is described below.

CCR3-Receptor Binding Protocol

Millipore filter plates (#MABVN1250) are treated with 5 mg/ml protaminein phosphate buffered saline, pH 7.2, for ten minutes at roomtemperature. Plates are washed three times with phosphate bufferedsaline and incubated with phosphate buffered saline for thirty minutesat room temperature. For binding, 50 ml of binding buffer (0.5% bovineserum albumen, 20 mM HEPES buffer and 5 mM magnesium chloride in RPMI1640 media) with or without a test concentration of a compound presentat a known concentration is combined with 50 ml of 125-I labeled humaneotaxin (to give a final concentration of 150 pM radioligand) and 50 mlof cell suspension in binding buffer containing 5×10⁵ total cells. Cellsused for such binding assays can include cell lines transfected with agene expressing CCR3 such as that described by Daugherty et al. (1996),isolated human eosinophils such as described by Hansel et al. (1991) orthe AML14.3D10 cell line after differentiation with butyric acid asdescribed by Tiffany et al. (1998). The mixture of compound, cells andradioligand are incubated at room temperature for thirty minutes. Platesare placed onto a vacuum manifold, vacuum applied, and plates washedthree times with binding buffer with 0.5M NaCl added. The plastic skirtis removed from the plate, the plate allowed to air dry, the wells punchout and CPM counted. The percent inhibition of binding is calculatedusing the total count obtained in the absence of any competing compoundor chemokine ligand and the background binding determined by addition of100 nM eotaxin in place of the test compound.

The utility of the compounds in accordance with the present invention asinhibitors of the migration of eosinophils or cell lines expressing thechemokine receptors may be demonstrated by methodology known in the art,such as the chemotaxis assay disclosed by Bacon et al., Brit. J.Pharmacol., 95, 966-974 (1988). In particular, the compound of thepresent invention have activity in inhibition of the migration ofeosinophils in the aforementioned assays. As used herein, “activity” isintended to mean a compound demonstrating an IC50 of 10 mM or lower inconcentration when measured in the aforementioned assays. Such a resultis indicative of the intrinsic activity of the compounds as modulatorsof chemokine receptor activity. A human eosinophil chemotaxis assayprotocol is described below.

Human Eosinophil Chemotaxis Assay

Neuroprobe MBA96 96-well chemotaxis chambers with Neuroprobepolyvinylpyrrolidone-free polycarbonate PFD5 5-micron filters in placeare warmed in a 37° C. incubator prior to assay. Freshly isolated humaneosinophils, isolated according to a method such as that described byHansel et al. (1991), are suspended in RPMI 1640 with 0.1% bovine serumalbumin at 1×10⁶ cells/ml and warmed in a 37° C. incubator prior toassay. A 20 nM solution of human eotaxin in RPMI 1640 with 0.1% bovineserum albumin is warmed in a 37° C. incubator prior to assay. Theeosinophil suspension and the 20 nM eotaxin solution are each mixed 1:1with prewarmed RPMI 1640 with 0.1% bovine serum albumin with or withouta dilution of a test compound that is at two fold the desired finalconcentration. These mixtures are warmed in a 37° C. incubator prior toassay. The filter is separated from the prewarmed Neuroprobe chemotaxischamber and the eotaxin/compound mixture is placed into a PolyfiltronicsMPC 96 well plate that has been placed in the bottom part of the NeuroProbe chemotaxis chamber. The approximate volume is 370 microliters andthere should be a positive meniscus after dispensing. The filter isreplaced above the 96 well plate, the rubber gasket is attached to thebottom of the upper chamber, and the chamber assembled. A 200 ml volumeof the cell suspension/compound mixture is added to the appropriatewells of the upper chamber. The upper chamber is covered with a platesealer, and the assembled unit placed in a 37° C. incubator for 45minutes. After incubation, the plate sealer is removed and all remainingcell suspension is aspirated off. The chamber is disassembled and, whileholding the filter by the sides at a 90-degree angle, unmigrated cellsare washed away using a gentle stream of phosphate buffered salinedispensed from a squirt bottle and then the filter wiped with a rubbertipped squeegee. The filter is allowed to completely dry and immersedcompletely in Wright Giemsa stain for 30-45 seconds. The filter isrinsed with distilled water for 7 minutes, rinsed once with waterbriefly, and allowed to dry. Migrated cells are enumerated bymicroscopy.

Mammalian chemokine receptors provide a target for interfering with orpromoting immune cell function in a mammal, such as a human. Compoundsthat inhibit or promote chemokine receptor function are particularlyuseful for modulating immune cell function for therapeutic purposes.Accordingly, the present invention is directed to compounds which areuseful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation orinfectious disease. As a result, one or more inflammatory process, suchas leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, is inhibited. Forexample, eosinophilic infiltration to inflammatory sites (e.g., inasthma or allergic rhinitis) can be inhibited according to the presentmethod. In particular, the compound of the following examples hasactivity in blocking the migration of cells expressing the CCR-3receptor using the appropriate chemokines in the aforementioned assays.As used herein, “activity” is intended to mean a compound demonstratingan IC50 of 10 mM or lower in concentration when measured in theaforementioned assays. Such a result is also indicative of the intrinsicactivity of the compounds as modulators of chemokine receptor activity.

Similarly, an instant compound which promotes one or more functions ofthe mammalian chemokine receptor (e.g., a human chemokine) asadministered to stimulate (induce or enhance) an immune or inflammatoryresponse, such as leukocyte emigration, adhesion, chemotaxis, exocytosis(e.g., of enzymes, histamine) or inflammatory mediator release,resulting in the beneficial stimulation of inflammatory processes. Forexample, eosinophils can be recruited to combat parasitic infections. Inaddition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for an instant compoundwhich promotes one or more functions of the mammalian chemokine receptorif one contemplates the delivery of sufficient compound to cause theloss of receptor expression on cells through the induction of chemokinereceptor internalization or the delivery of compound in a manner thatresults in the misdirection of the migration of cells.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, agonism, partialantagonism and/or partial agonism.

Diseases or conditions of human or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV.

Diseases or conditions of humans or other species which can be treatedwith promoters of chemokine receptor function, include, but are notlimited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larvamigraines (Ancylostona braziliense, Ancylostoma caninum). The compoundsof the present invention are accordingly useful in the prevention andtreatment of a wide variety of inflammatory, infectious andimmunoregulatory disorders and diseases. In addition, treatment of theaforementioned inflammatory, allergic and autoimmune diseases can alsobe contemplated for promoters of chemokine receptor function if onecontemplates the delivery of sufficient compound to cause the loss ofreceptor expression on cells through the induction of chemokine receptorinternalization or delivery of compound in a manner that results in themisdirection of the migration of cells.

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

Preferably, the compounds of the present invention are used to treat orprevent disorders selected from asthma, allergic rhinitis, atopicdermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis,bullous pemphigoid, helminthic parasitic infections, allergic colitis,eczema, conjunctivitis, transplantation, familial eosinophilia,eosinophilic cellulitis, eosinophilic pneumonias, eosinophilicfasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIVinfection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin'sdisease, and colonic carcinoma.

More preferably, the compounds are used to treat or prevent disordersselected from asthma, allergic rhinitis, atopic dermatitis, andinflammatory bowel diseases. Even more preferably, the compounds areused to treat asthma.

Combined therapy to prevent and treat inflammatory, infectious andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis, and those pathologies noted above is illustrated bythe combination of the compounds of this invention and other compoundswhich are known for such utilities. For example, in the treatment orprevention of inflammation, the present compounds may be used inconjunction with an anti-inflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor,an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumornecrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalanti-inflammatory agent, a phosphodiesterase inhibitor, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha and thelike. Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine;and antitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compound of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention. Examples of other active ingredients that may becombined with a compound of the present invention, either administeredseparately or in the same pharmaceutical compositions, include, but arenot limited to: (a) integrin antagonists such as those for selectins,ICAMs and VLA-4; (b) steroids such as beclomethasone,methylprednisolone, betamethasone, prednisone, dexamethasone, andhydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus,rapamycin and other FK-506 type immunosuppressants; (d) antihistamines(H1-histamine antagonists) such as bromopheniramine, chlorpheniramine,dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine,fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as b2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (I) other antagonists of thechemokine receptors; (j) cholesterol lowering agents such as HMG-COAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvsatatin, and other statins), sequestrants(cholestyramine and colestipol), nicotonic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (k) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone ad pioglitazone); (1) preparations ofinterferons (interferon alpha-2a, interferon-2B, interferon alpha-N3,interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m)antiviral compounds such as efavirenz, nevirapine, indinavir,ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) othercompound such as 5-aminosalicylic acid an prodrugs thereof,antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents. The weight ratio of the compound of thepresent invention to the second active ingredient may be varied and willdepend upon the effective doses of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the present invention is combined with an NSAID the weight ratio ofthe compound of the present invention to the NSAID will generally rangefrom about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient,and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration-will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

What is claimed is:
 1. A compound of formula I:

or stereoisomers or pharmaceutically acceptable salts thereof, wherein:J is selected from CH₂ and CHR⁵; K and L are independently selected fromCR⁵R⁶ and CR⁶R⁶; M, at each occurrence, is selected from CR⁵R⁶ andCR⁶R⁶; with the proviso that at least one of J, K, L, or M contains anR⁵; X is selected from (CR⁷′R⁷′)_(q)—S—(CR⁷′R⁷′)_(q),(CR⁷′R⁷′)_(q)—O—(CR⁷′R⁷′)_(q), (CR⁷′R⁷′)_(q)—NR⁷—(CR⁷′R⁷′)_(q),(CR⁷′R⁷′)_(r)—C(O)—(CR⁷′R⁷′)_(q), C₁₋₆ alkylene substituted with 0-5 R⁷,C₂₋₁₀ alkenylene substituted with 0-5 R⁷, C₂₋₁₀ alkynylene substitutedwith 0-5 R⁷, and (CR⁷R⁷)_(t)—A—(CR⁷R⁷)_(t) substituted with 0-3 R⁸; withthe proviso that when R⁷ or R⁷′ is bonded to the same carbon as Y, R⁷ isnot halogen, cyano, or bonded through a heteroatom; A is C₃₋₆carbocyclic residue; Y is selected from NR¹¹C(═O)NR¹¹, NR¹¹C(═S)NR¹¹,NR¹¹C(═NR^(a))NR¹¹, NR¹¹C(═CHCN)NR¹¹, NR¹¹C(═CHNO₂)NR¹¹,NR¹¹C(═C(CN)₂)NR¹¹, NR¹¹, C(O), S(O)₂NR¹¹, NR¹¹S(O)₂, NR¹¹S(O)₂NR¹¹,C(O)NR¹¹, NR¹¹C(O), NR¹¹C(O)O, OC(O)NR¹¹, and S(O)_(p); R^(a) isselected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, OH, CN, O—C₁₋₆ alkyl, and(CH₂)_(w)phenyl; R¹ is selected from a (CR¹′R¹″)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-5 R⁹ and a (CR¹′R¹″)_(r)—5-10 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R⁹; R¹′ and R¹″, at each occurrence, areselected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and phenyl; R²,at each occurrence, is selected from H, C₁₋₈ alkyl,(CR²′R²″)_(q)NR^(12a)R^(12a)′, (CR²′R²″)_(w)OH,(CR²′R²″)_(w)O(CR²′R²″)_(r)R^(12d), (CR²′R²″)_(q)SH, (CR²′R²″)_(r)C(O)H,(CR²′R²″)_(q)S(CR²′R²″)_(r)R^(12d), (CR²′R²″)_(r)C(O)OH,(CR²′R²″)_(r)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)NR^(12a)C(NR^(a))NR^(12a)R^(12a)′,(CR²′R²″)_(r)C(NR^(a))NR^(12a)R^(12a)′, (CR²′R²″)_(r)C(NR^(a))R^(12b),(CR²′R²″)_(r)C(O)NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(r)C(O)O(CR²′R²″)_(r)R^(12d),(CR²′R²″)_(w)OC(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)S(O)_(p)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)S(O)₂NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)S(O)₂(CR²′R²″)_(r)R^(12b), C₁₋₆ haloalkyl, C₂₋₈alkenyl substituted with 0-3 R^(12c), C₂₋₈ alkynyl substituted with 0-3R^(12c), a (CR²′R²″)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(12c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(12c);alternatively, R² is an amino acid residue; R²′ and R²″, at eachoccurrence, are selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CF₂)_(r)CF₃, (CH₂)_(r)CN, (CH₂)_(r)NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)NR^(2a)R^(2a)′, (CH₂)_(r)OH, (CH₂)_(r)OR^(2b), (CH₂)_(r)SH,(CH₂)_(r)SR^(2b), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(2b),(CH₂)_(r)C(O)NR^(2a)R^(2a)′, (CH₂)_(r)NR^(2d)C(O)R^(2a),(CH₂)_(r)C(O)OR^(2b), (CH₂)_(r)OC(O)R^(2b), (CH₂)_(r)S(O)_(p)R^(2b),(CH₂)_(r)S(O)₂NR^(2a)R^(2a)′, (CH₂)NR^(2d)S(O)₂R^(2b), C₁₋₆ haloalkyl, a(CR²′R²″)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(2c), anda (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(2c); R^(2a) andR^(2a)′, at each occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(2c); R^(2b), at eachoccurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenylsubstituted with 0-3 R^(2c); R^(2c), at each occurrence, is selectedfrom C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(2d)R^(2d),(CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl, (CH₂)_(r)SC₁₋₄ alkyl,(CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(2b), (CH₂)_(r)C(O)NR^(2d)R^(2d),(CH₂)_(r)NR^(2d)C(O)R^(7a), (CH₂)_(r)C(O)OC₁₋₄ alkyl,(CH₂)_(r)OC(O)R^(2b), (CH₂)_(r)C(═NR^(2d))NR^(2d)R^(2d),(CH₂)_(r)S(O)_(p)R^(2d), (CH₂)_(r)NHC(═NR^(2d))NR^(2d)R^(2d),(CH₂)_(r)S(O)₂NR^(2d)R^(2d), (CH₂)_(r)NR^(2d)S(O)₂R^(2b), and(CH₂)_(r)phenyl substituted with 0-3 R^(9e); R^(2d), at each occurrence,is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R³ is selected fromH, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl,(CF₂)_(r)CF₃, (CH₂)_(q)NR^(3a)R^(3a)′, (CH₂)_(q)OH, (CH₂)_(q)OR^(3b),(CH₂)_(q)SH, (CH₂)_(q)SR^(3b), (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(3b),(CH₂)_(r)C(O)NR^(3a)R^(3a)′, (CH₂)_(q)NR^(3d)C(O)R^(3a),(CH₂)_(r)C(O)OR^(3b), (CH₂)_(q)OC(O)R^(3b), (CH₂)_(r)S(O)_(p)R^(3b),(CH₂)_(r)S(O)₂NR^(3a)R^(3a)′, (CH₂)_(q)NR^(3d)S(O)₂R^(3b), and(CH₂)_(r)-phenyl substituted with 0-3 R^(3c); R^(3a) and R^(3a) , ateach occurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, andphenyl substituted with 0-3 R^(3c); R^(3b), at each occurrence, isselected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with0-3 R^(3c); R^(3c), at each occurrence, is selected from C₁₋₆ alkyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl, and (CH₂)_(r)NR^(3d)R^(3d);R^(3d), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R⁴ is absent, taken with the nitrogen to which it isattached to form an N-oxide, or taken with the nitrogen to which it isattached to form a quaternary salt comprising a compound of formula (I)and a counterion and is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CH₂)_(q)C(O)R^(4b),(CH₂)_(q)C(O)NR^(4a)R^(4a)′, (CH₂)_(q)C(O)OR^(4b), and a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(4c); R^(4a) and R^(4a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, and phenyl; R^(4b), at each occurrence, is selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, (CH₂)_(r)C₃₋₆ cycloalkyl, C₂₋₈ alkynyl, andphenyl; R^(4c), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4a)R^(4a)′, and (CH₂)_(r)phenyl; R⁵ is selected from a(CR⁵′R⁵″)_(t)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R¹⁰ and a(CR⁵′R⁵″)_(t)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R¹⁰; R⁵′ andR⁵″, at each occurrence, are selected from H, C₁₋₆ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, and phenyl; alternatively, R⁵ and R⁶ join to form a 5, 6, or7-membered spirocycle, containing 0-3 heteroatoms selected from N, O,and S, substituted with 0-3 R¹⁶; R⁶, at each occurrence, is selectedfrom H, C₁₋₄ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, (CF₂)_(r)CF₃, CN, (CH₂)_(r)NR^(6a)R^(6a)′, (CH₂)_(r)OH,(CH₂)_(r)OR^(6b), (CH₂)_(r)SH, (CH₂)_(r)SR^(6b), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)R^(6b), (CH₂)_(r)C(O)NR^(6a)R^(6a)′,(CH₂)_(r)NR^(6d)C(O)R^(6a), (CH₂)_(r)C(O)OR^(6b), (CH₂)_(r)OC(O)R^(6b),(CH₂)_(r)S(O)_(p)R^(6b), (CH₂)_(r)S(O)₂NR^(6a)R^(6a)′,(CH₂)_(r)NR^(6d)S(O)₂R^(6b), and (CH₂)_(t)phenyl substituted with 0-3R^(6c); R^(6a) and R^(6a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl substituted with 0-3 R^(6c);R^(6b), at each occurrence, is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(6c); R^(6c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅alkyl, and (CH₂)_(r)NR^(6d)R^(6d); R^(6d), at each occurrence, isselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R⁷, at eachoccurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F,Cl, Br, I, (CH₂)_(r)OH, (CH₂)_(r)SH, (CH₂)_(r)OR^(7d), (CH₂)_(r)SR^(7d),(CH₂)_(r)NR^(7a)R^(7a)′, C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₆ carbocyclicresidue substituted with 0-3 R^(7c); R^(7a) and R^(7a)′, at eachoccurrence, are selected from H, C₁₋₆alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl,and phenyl substituted with 0-3 R^(7e); R^(7b), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆cycloalkyl, and phenyl substituted with 0-3 R^(7e); R^(7c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₆ alkyl,OH, SH, (CH₂)_(r)SC₁₋₆ alkyl, (CH₂)_(r)NR^(7d)R^(7d), C(O)C₁₋₆ alkyl,and (CH₂)_(r)phenyl; R^(7d), at each occurrence, is selected from H,C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R^(7e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;R^(7f), at each occurrence, is selected from H, C₁₋₅ alkyl, C₃₋₆cycloalkyl, and phenyl; R⁷′, at each occurrence, is selected from H,C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(q)OH, (CH₂)_(q)SH,(CH₂)_(q)OR^(7b), (CH₂)_(q)SR^(7b), (CH₂)_(q)NR^(7a)R^(7a)′,(CH₂)_(r)C(O)OH, C₁₋₆ haloalkyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(7c); R⁸, at each occurrence, is selected fromC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl,Br, I, F, NO₂, CN, (CHR′)_(r)NR^(8a)R^(8a)′, (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(8d), (CHR′)_(r)SH, (CHR′)_(r)C(O)H,(CHR′)_(r)S(CHR′)_(r)R^(8d), (CHR′)_(r)C(O)OH,(CHR′)_(r)C(O)(CHR′)_(r)R^(8b), (CHR′)_(r)C(O)NR^(8a)R^(8a)′,(CHR′)_(r)NR^(8f)C(O)(CHR′)_(r)R^(8b), (CHR′)_(r)C(O)O(CHR′)_(r)R^(8d),(CHR′)_(r)OC(O)(CHR′)_(r)R^(8b), (CHR′)_(r)C(═NR^(8f))NR^(8a)R^(8a)′,(CHR′)_(r)NHC(═NR^(8f))NR^(8f)R^(8f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(8b), (CHR′)_(r)S(O)₂NR^(8a)R^(8a),(CHR′)_(r)NR^(8f)S(O)₂(CHR′)_(r)R^(8b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(8e); R′, at each occurrence, isselected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(8e); R^(8a) andR^(8a)′, at each occurrence, are selected from H, C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(8e), and a (CH₂)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-2 R^(8e); R^(8b), at each occurrence, is selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(8e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(8e); R^(8d), at each occurrence, is selected from C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(8e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(8e), and a(CH₂)_(r)5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(8e); R^(8e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(8f)R^(8f), and (CH₂)_(r)phenyl; R^(8f), at each occurrence,is selected from H, C₁₋₅ alkyl, C₃₋₆ cycloalkyl, and phenyl; R⁹, at eachoccurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(9a)R^(9a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(9d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(9d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(9b),(CHR′)_(r)C(O)NR^(9a)R^(9a)′, (CHR′)_(r)NR^(9f)C(O)(CHR′)_(r)R^(9b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(9d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(9b),(CHR′)_(r)C(═NR^(9f))NR^(9a)′, (CHR′)_(r)NHC(═NR^(9f))NR^(9f)R^(9f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(9b), (CHR′)_(r)S(O)₂NR^(9a)R^(9a)′,(CHR′)_(r)NR^(9f)S(O)₂(CHR′)_(r)R^(9b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂8 alkynyl substituted with 0-3 R′,(CHR′)_(r)phenyl substituted with 0-3 R^(9e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(9e); R^(9a) and R^(9a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(9e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(9e); R^(9b), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3 R^(9e), and(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(9e); R^(9d), at eachoccurrence, is selected from C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₆ alkylsubstituted with 0-3 R^(9e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(9e), and a (CH₂)_(r)5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(9e); R^(9e), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br,I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅alkyl, (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl; R^(9f), at eachoccurrence, is selected from H, C₁₋₅ alkyl, C₃₋₆ cycloalkyl, and phenyl;R¹⁰, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CHR′)_(r)NR^(10a)R^(10a)′, (CHR′)_(r)OH, (CHR′)_(r)O(CHR′)_(r)R^(10d),(CHR′)_(r)SH, (CHR′)_(r)C(O)H, (CHR′)_(r)S(CHR′)_(r)R^(10d),(CHR′)_(r)C(O)OH, (CHR′)_(r)C(O)(CHR′)_(r)R^(10b),(CHR′)_(r)C(O)NR^(10a)R^(10a)′, (CHR′)_(r)NR^(10f)C(O)(CHR′)_(r)R^(10b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(10d), (CHR′)_(r)OC(O)(CHR′)_(r)R^(10b),(CHR′)_(r)C(═NR^(10f))NR^(10a)R^(10a)′,(CHR′)_(r)NHC(═NR^(10f))NR^(10f)R^(10f),(CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(10b), (CHR′)_(r)S(O)₂NR^(10a)R^(10a)′,(CHR′)_(r)NR^(10f)S(O)₂(CHR′)_(r)R^(10b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CHR′)_(r)phenyl substituted with 0-3 R^(10e); R^(10a) and R^(10a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(10e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(10e);R^(10b), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(10e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(10e);R^(10d), at each occurrence, is selected from C₂₋₈ alkenyl, C₂₋₈alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(10e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(10e), and a (CH₂)_(r)5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(10e); R^(10e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(10f)R^(10f), and(CH₂)_(r)phenyl; R^(10f), at each occurrence, is selected from H, C₁₋₅alkyl, C₃₋₆ cycloalkyl, and phenyl; R¹¹, at each occurrence is selectedfrom H, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with0-5 R^(11a); R^(11a), at each occurrence, is selected from C₁₋₄ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F,(CF₂)_(r)CF₃, NO₂, CN, (CH₂)_(r)NR^(11b)R^(11b), (CH₂)_(r)OH,(CH₂)_(r)OR^(11c), (CH₂)_(r)SH, (CH₂)_(r)SR^(11c), (CH₂)_(r)C(O)R^(11b),(CH₂)_(r)C(O)NR^(11b)R^(11b), (CH₂)_(r)NR^(11b)C(O)R^(11b),(CH₂)_(r)C(O)OR^(11b), (CH₂)_(r)OC(O)R^(11c),(CH₂)_(r)CH(═NR^(11b))NR^(11b)R^(11b),(CH₂)_(r)NHC(═NR^(11b))NR^(11b)R^(11b), (CH₂)_(r)S(O)_(p)R^(11c),(CH₂)_(r)S(O)₂NR^(11b)R^(11b), (CH₂)_(r)NR^(11b)S(O)₂R^(11c), and(CH₂)_(r)phenyl; R^(11b), at each occurrence, is selected from H, C₁₋₆alkyl, C₃₋₆ cycloalkyl, and phenyl; R^(11c), at each occurrence, isselected from C₁₋₅ alkyl, C₃₋₆ cycloalkyl, and phenyl; R^(12a) andR^(12a)′, at each occurrence, are selected from H, C₁₋₆ alkylsubstituted with 0-3 R^(12e), C₂₋₈ alkenyl, C₂₋₈ alkynyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(12e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(12e); R^(12b), ateach occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(12e), and (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(12e);R^(12c), at each occurrence, is selected from C₁₋₄ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, (CF₂)_(r)CF₃, NO₂,CN, (CH₂)_(r)NR^(12f)R^(12f), (CH₂)_(r)OH, (CH₂)_(r)OC₁₋₄ alkyl,(CH₂)_(r)SC₁₋₄ alkyl, (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)R^(12b),(CH₂)_(r)C(O)NR^(12f)R^(12f), (CH₂)_(r)NR^(12f)C(O)R^(12a),(CH₂)_(r)C(O)OC₁₋₄ alkyl, (CH₂)_(r)OC(O)R^(12b),(CH₂)_(r)C(═NR^(12f))NR^(12f)R^(12f), (CH₂)_(r)S(O)_(p)R^(12b),(CH₂)_(r)NHC(═NR^(12f))NR^(12f)R^(12f), (CH₂)_(r)S(O)₂NR^(12f)R^(12f),(CH₂)_(r)NR^(12f)S(O)₂R^(12b), and (CH₂)_(r)phenyl substituted with 0-3R^(12e); R^(12d), at each occurrence, is selected from C₂₋₈ alkenyl,C₂₋₈ alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(12e), a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-3 R^(12e), and a (CH₂)_(r)5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(12e); R^(12e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and(CH₂)_(r)phenyl; R^(12f), at each occurrence, is selected from H, C₁₋₅alkyl, C₃₋₆ cycloalkyl, and phenyl; w is selected from 2, 3, 4, and 5; vis 1; t is selected from 0, 1 and 2; r is selected from 0, 1, 2, 3, 4,and 5; q is selected from 1, 2, 3, 4, and 5; and p is selected from 1,2, and
 3. 2. The compound according to claim 1, wherein: when v is 0, Lis CH₂; when v is 1, M is CH₂; or when v is 2, the M adjacent to thecarbon bearing R³ is CH₂.
 3. The compound according to claim 2, wherein:R³ is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, and C₂-8 alkynyl; R⁴ isabsent, taken with the nitrogen to which it is attached to form anN-oxide, or taken with the nitrogen to which it is attached to form aquaternary salt comprising a compound of formula (I) and a counterionand is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)-phenyl substituted with 0-3 R^(4c); R^(4c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, CF₃, (CH₂)_(r)OC₁₋₅ alkyl,(CH₂)_(r)OH; R⁶, at each occurrence, is selected from H, C₁₋₄ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, (CF₂)_(r)CF₃, (CH₂)_(r)OH, (CH₂)_(r)OR^(6b),and (CH₂)_(t)phenyl substituted with 0-3 R^(6c); R^(6c), at eachoccurrence, is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, (CH₂)_(r)OH, (CH₂)_(r)SC₁₋₅alkyl, and (CH₂)_(r)NR^(6d)R^(6d); R^(6d), at each occurrence, isselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; q is selected from 1,2, and 3; and r is selected from 0, 1, 2, and
 3. 4. The compoundaccording to claim 3, wherein: A is selected from phenyl, cyclohexyl,cyclopentyl, and cyclopropyl; R⁷, at each occurrence, is selected fromC₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, F, Cl, Br, I, (CH₂)_(r)OH,(CH₂)_(r)OR^(7d), (CH₂)_(r)NR^(7a)R^(7a)′, (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)-phenyl substituted with 0-3 R^(7e); R^(7a) and R^(7a)′, ateach occurrence, are selected from H, C₁₋₆ alkyl; R^(7d), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl;R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl; R^(7e) is selected from Hand C₁₋₆ alkyl; R⁷′ is H; R⁸, at each occurrence, is selected from C₁₋₈alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F,(CH₂)_(r)NR^(8a)R^(8a)′, NO₂, CN, OH, (CH₂)_(r)OR^(8d),(CH₂)_(r)C(O)R^(8b), (CH₂)_(r)C(O)NR^(8a)R^(8a)′,(CH₂)_(r)NR^(8f)C(O)R^(8b), (CH₂)_(r)S(O)_(p)R^(8b),(CH₂)_(r)S(O)₂NR^(8a)R^(8a)′, (CH₂)_(r)NR^(8f)S(O)₂R^(8b), and(CH₂)_(r)phenyl substituted with 0-3 R^(8e); R^(8a) and R^(8a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(8e); R^(8b), at each occurrence,is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenylsubstituted with 0-3 R^(8e); R^(8d), at each occurrence, is selectedfrom C₁₋₆ alkyl and phenyl; R^(8e), at each occurrence, is selected fromC₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅alkyl; and R^(8f), at each occurrence, is selected from H and C₁₋₅alkyl; and R¹¹, at each occurrence, is selected from H, and C₁₋₈ alkyl.5. The compound according to claim 4, wherein: R¹ is selected from a(CR¹′H)_(r)-carbocyclic residue substituted with 0-5 R⁹, wherein thecarbocyclic residue is selected from phenyl, C₃₋₆ cycloalkyl, napthyl,and adamantyl; and a (CR¹′H)_(r)-heterocyclic system substituted with0-3 R⁹, wherein the heterocyclic system is selected from pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl; and R⁵ is selected from (CR⁵′H)_(t)-phenylsubstituted with 0-5 R¹⁰; and a (CR⁵′H)_(t)-heterocyclic systemsubstituted with 0-3 R¹⁰, wherein the heterocyclic system is selectedfrom pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
 6. Thecompound according to claim 5, wherein M is CH₂, and J is CH₂.
 7. Thecompound according to claim 6, wherein R³ is H and R⁴ is absent.
 8. Thecompound according to claim 7, wherein: R⁹, at each occurrence, isselected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F,(CH₂)_(r)NR^(9a)R^(9a)′, NO₂, CN, OH, (CH₂)_(r)OR^(9d),(CH₂)_(r)C(O)R^(9b), (CH₂)_(r)C(O)NR^(9a)R^(9a)′,(CH₂)_(r)NR^(9f)C(O)R^(9b), (CH₂)_(r)S(O)_(p)R^(9b),(CH₂)_(r)S(O)₂NR^(9a)R^(9a)′, (CH₂)_(r)NR^(9f)S(O)₂R^(9b),(CH₂)_(r)phenyl substituted with 0-3 R^(9e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-2 R^(9e); R^(9a) and R^(9a)′, at eachoccurrence, are selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and(CH₂)_(r)phenyl substituted with 0-3 R^(9e); R^(9b), at each occurrence,is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenylsubstituted with 0-3 R^(9e); R^(9d), at each occurrence, is selectedfrom C₁₋₆ alkyl and phenyl; R^(9e), at each occurrence, is selected fromC₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅alkyl; and R^(9f), at each occurrence, is selected from H, and C₁₋₅alkyl; R¹⁰, at each occurrence, is selected from C₁₋₈ alkyl,(CH₂)_(r)C₃₋₆ cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(10a)R^(10a)′,NO₂, CN, OH, (CH₂)_(r)OR^(10d), (CH₂)_(r)C(O)R^(10b),(CH₂)_(r)C(O)NR^(10a)R^(10a)′, (CH₂)_(r)NR^(10f)C(O)R^(10b),(CH₂)_(r)S(O)_(p)R^(10b), (CH₂)_(r)S(O)₂NR^(10a)R^(10a)′,(CH₂)_(r)NR^(10f)S(O)₂R^(10b), and (CH₂)_(r)phenyl substituted with 0-3R^(10e); R^(10a) and R^(10a)′, at each occurrence, are selected from H,C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3R^(10e); R^(10b), at each occurrence, is selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substituted with 0-3 R^(10e);R^(10d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;R^(10e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and R^(10f), ateach occurrence, is selected from H, and C₁₋₅ alkyl.
 9. The compoundaccording to claim 8, wherein K is CH₂, L is CHR⁵, wherein R⁵ issubstituted with 0-3 R¹⁰.
 10. The compound according to claim 9, whereinR⁵ is (CH₂)-phenyl substituted with 0-3 R¹⁰.
 11. The compound accordingto claim 10, wherein R¹ is phenyl substituted with 0-3 R⁹.
 12. Thecompound according to claim 10, wherein: X is propylene substituted with0-3 R⁷; and R⁷, at each occurrence, is selected from C₁₋₃ alkyl,(CH₂)_(r)OH, (CH₂)_(r)OR^(7d), (CH₂)_(r)C₃₋₆ cycloalkyl, and(CH₂)_(r)-phenyl substituted with 0-3 R^(7e); R^(7d), at eachoccurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and phenyl;R^(7e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, (CH₂)_(r)NR^(7f)R^(7f);and R^(7f) is selected from H and C₁₋₆ alkyl.
 13. The compound accordingto claim 12, wherein: R², at each occurrence, is selected from H, C₁₋₈alkyl, (CR²′R^(2″))_(q)NR^(12a)R^(12a)′, (CR²′R²″)_(w)OH,(CR²′R²″)_(w)O(CR²′R²″)_(r)R^(12d),(CR²′R²″)_(r)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)NR^(12a)C(NR^(a))NR^(12a)R^(12a)′,(CR²′R²″)_(r)C(O)NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)S(O)₂NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)S(O)₂(CR²′R²″)_(r)R^(12b), C₁₋₆ haloalkyl, C₂₋₈alkenyl substituted with 0-3 R^(12c), C₂₋₈ alkynyl substituted with 0-3R^(12c), a (CR²′R²″)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3R^(12c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(12c);alternatively, R² is an amino acid residue; and R²′ and R²″, at eachoccurrence, are selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl, (CH₂)_(r)OH,(CH₂)_(r)OR^(2b), (CH₂)_(r)C(O)R^(2b), (CH₂)_(r)C(O)NR^(2a)R^(2a)′,(CH₂)_(r)NR^(2d)C(O)R^(2a).
 14. The compound according to claim 12,wherein X is unsubstituted propylene.
 15. The compound according toclaim 12, wherein: R⁵ is substituted with 0-2 R¹⁰; R¹⁰, at eachoccurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆ cycloalkyl, CF₃,Cl, Br, I, F, C(O)C₁₋₄ alkyl, (CH₂)_(r)NR^(10a)R^(10a)′, CN, OH, OCF₃,(CH₂)_(r)OR^(10d); R^(10a) and R¹⁰′, at each occurrence, are selectedfrom H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; and R^(10d) is C₁₋₆ alkyl. 16.The compound according to claim 15 wherein R¹⁰ is fluoro.
 17. Thecompound according to claim 12 wherein: R¹ is substituted with 0-2 R⁹;R⁹, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, F, NO₂, CN, (CHR′)_(r)NR^(9a)R^(9a)′, (CHR′)_(r)OH,(CHR′)_(r)O(CHR′)_(r)R^(9d), (CHR′)_(r)C(O)(CHR′)_(r)R^(9b),(CHR′)_(r)C(O)NR^(9a)R^(9a)′, (CHR′)_(r)NR^(9f)C(O)(CHR′)_(r)R^(9b),(CHR′)_(r)C(O)O(CHR′)_(r)R^(9d), (CHR′)_(r)S(O)_(p)(CHR′)_(r)R^(9b),(CHR′)_(r)S(O)₂NR^(9a)R^(9a)′, (CHR′)_(r)NR^(9f)S(O)₂(CHR′)_(r)R^(9b),CF₃, OCF₃, (CHR′)_(r)phenyl substituted with 0-3 R^(9e), and a(CH₂)_(r)5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(9e); R^(9a) andR^(9a)′, at each occurrence, are selected from H, C₁₋₆ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(9e), and a (CH₂)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-2 R^(9e); R^(9b), at each occurrence, is selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, a (CH₂)_(r)-C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(9e), and (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(9e); R^(9d), at each occurrence, is selected from C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₆ alkyl substituted with 0-3 R^(9e), a(CH₂)_(r)-C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(9e), and a(CH₂)_(r)5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(9e); R^(9e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl; and R^(9f), at eachoccurrence, is selected from H, C₁₋₅ alkyl, C₃₋₆ cycloalkyl, and phenyl.18. The compound according to claim 17, wherein R¹ is phenyl substitutedwith R⁹ in the 3 and 5 positions.
 19. The compound according to claim18, wherein: R⁹, at each occurrence, is selected from C(O)R^(9b),C(O)OR^(d), C(O)OH, CN, and a (CH₂)_(r)5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-2 R⁹e.
 20. The compound according to claim 16, wherein X isunsubstituted propylene.
 21. The compound according to claim 18, whereinX is unsubstituted propylene.
 22. The compound according to claim 20,wherein: R², at each occurrence, is selected from H, C₁₋₈ alkyl,(CR²′R²″)_(q)NR^(12a)R^(12a)′, (CR²′R²″)_(w)OH,(CR²′R²″)_(w)O(CR²′R²″)_(r)R^(12d),(CR²′R²″)_(r)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)NR^(12a)C(NR^(a))NR^(12a)R^(12a)′,(CR²′R²″)_(r)C(O)NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)S(O)₂NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)S(O)₂(CR²′R²″)_(r)R^(12b), C₁₋₆ haloalkyl, C₂₋₈alkenyl substituted with 0-3 R^(12c), C₂₋₈ alkynyl substituted with 0-3R^(12c), a (CR²′R²″)_(r)C₃₋₁₀ carbocyclic residue substituted with 0-3R^(12c), and a (CH₂)_(r)-5-10 membered heterocyclic system containing1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R^(12c);alternatively, R² is an amino acid residue; and R²′ and R²″, at eachoccurrence, are selected from H, C₁₋₈ alkyl, C₂₋₈ alkenyl, (CH₂)_(r)OH,(CH₂)_(r)OR^(2b), (CH₂)_(r)C(O)R^(2b), (CH₂)_(r)C(O)NR^(2a)R^(2a)′, and(CH₂)_(r)NR^(2d)C(O)R^(2a).
 23. The compound according to claim 2,wherein Y is selected from NR¹¹C(═S)NR¹¹, NR¹¹C(═NR^(a))NR¹¹,NR¹¹C(═CHCN)NR¹¹, NR¹¹C(═CHNO₂)NR¹¹, NR¹¹C(═C(CN)₂)NR¹¹, NR¹¹, C(O),S(O)₂NR¹¹, NR¹¹S(O)₂, NR¹¹S(O)₂NR¹¹, C(O)NR¹¹, NR¹¹C(O), NR¹¹C(O)O,OC(O)NR¹¹, and S(O)_(p).
 24. The compound according to claim 23, whereinY is selected from NR¹¹C(═NR^(a))NR¹¹, NR¹¹C(═CHCN)NR¹¹,NR¹¹C(═CHNO₂)NR¹¹, and NR¹¹C(═C(CN)₂)NR¹¹.
 25. The compound according toclaim 12, wherein Y is selected from NR¹¹C(═S)NR¹¹, NR¹¹C(═NR^(a))NR¹¹,NR¹¹C(═CHCN)NR¹¹, NR¹¹C(═CHNO₂)NR¹¹, NR¹¹C(═C(CN)₂)NR¹¹, NR¹¹, C(O),S(O)₂NR^(11, NR) ¹¹S(O)₂, NR¹¹S(O)₂NR¹¹, C(O)NR¹¹, NR¹¹C(O), NR¹¹C(O)O,OC(O)NR¹¹, and S(O)_(p).
 26. The compound according to claim 25, whereinY selected from NR¹¹C(═NR^(a))NR¹¹, NR¹¹C(═CHCN)NR¹¹, NR¹¹C(═CHNO₂)NR¹¹,and NR¹¹C(═C(CN)₂)NR¹¹.
 27. The compound according to claim 26, wherein:Y is selected from NR¹¹C(═NCN)NR¹¹ and NR¹¹C(═C(CN)₂)NR¹¹; and R¹¹, ateach occurrence, is selected from H and C₁₋₆ alkyl.
 28. The compoundaccording to claim 14, wherein Y selected from NR¹¹C(═NR^(a))NR¹¹,NR¹¹C(═CHCN)NR¹¹, NR¹¹C(═CHNO₂)NR¹¹, and NR¹¹C(═C(CN)₂)NR¹¹.
 29. Thecompound according to claim 15, wherein X is unsubstituted propyl and Yis selected from NR¹¹C(═NR^(a))NR¹¹, NR¹¹C(═CHCN)NR¹¹,NR¹¹C(═CHNO₂)NR¹¹, and NR¹¹C(═C(CN)₂)NR¹¹.
 30. The compound according toclaim 29, wherein R¹⁰ is fluoro.
 31. The compound according to claim 30,wherein Y is selected from NHC(═NCN)NH and NHC(═C(CN)₂)NH.
 32. Thecompound according to claim 17, wherein X is unsubstituted propyl and Yis selected from NR¹¹C(═NR^(a))NR¹¹, NR¹¹C(═CHCN)NR¹¹,NR¹¹C(═CHNO₂)NR¹¹, and NR¹¹C(═C(CN)₂)NR¹¹.
 33. The compound according toclaim 32, wherein R¹ is phenyl substituted with R⁹ in the 3 and 5positions.
 34. The compound according to claim 33, wherein: R⁹, at eachoccurrence, is selected from C(O)R^(9b), C(O)OR^(d), C(O)OH, CN, and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(9e).
 35. The compoundaccording to claim 34, wherein Y is selected from NHC(═NCN)NH andNHC(═C(CN)₂)NH.
 36. The compound according to claim 28, wherein: R², ateach occurrence, is selected from H, C₁₋₈ alkyl, (CH₂)_(q)NR^(12a)R¹²a′,(CH₂)_(w)OH, (CH)_(w)O(CR²′R²″)_(r)R^(12d),(CR²′R²″)_(r)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)NR^(12a)C(NR^(a))NR^(12a)R^(12a)′,(CR²′R²″)_(r)C(O)NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)S(O)₂NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)S(O)₂(CR²′R²″)_(r)R^(12b); R²′ and R²″ are H; r isselected from 0, 1, and 2; and w and q are selected from 2 and
 3. 37.The compound according to claim 29, wherein: R², at each occurrence, isselected from H, C₁₋₈ alkyl, (CH₂)_(q)NR^(12a)R^(12a)′, (CH₂)_(w)OH,(CH)_(w)O(CR²′R²″)_(r)R^(12d), (CR²′R²″)_(r)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)NR^(12a)C(NR^(a))NR^(12a)R^(12a)′,(CR²′R²″)_(r)C(O)NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)S(O)₂NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)S(O)₂(CR²′R²″)_(r)R^(12b); R²′ and R²″ are H; r isselected from 0, 1, and 2; and w and q are selected from 2 and
 3. 38.The compound according to claim 32, wherein: R², at each occurrence, isselected from H, C₁₋₈ alkyl, (CH₂)_(q)NR^(12a)R¹²a′, (CH₂)_(w)OH,(CH)_(w)O(CR²′R²″)_(r)R^(12d), (CR²′R²″)_(r)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)NR^(12a)C(NR^(a))NR^(12a)R^(12a)′,(CR²′R²″)_(r)C(O)NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)C(O)(CR²′R²″)_(r)R^(12b),(CR²′R²″)_(w)S(O)₂NR^(12a)R^(12a)′,(CR²′R²″)_(q)NR^(12f)S(O)₂(CR²′R²″)_(r)R^(12b); R²′ and R²″are H; r isselected from 0, 1, and 2; and w and q are selected from 2 and
 3. 39.The compound according to claim 10, wherein: X is(CR⁷R⁷)_(t)—A—(CR⁷R⁷)_(t) substituted with 0-3 R⁸; R⁷, at eachoccurrence, is selected from C₁₋₃ alkyl, (CH₂)_(r)OH, (CH₂)_(r)OR^(7d),(CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)-phenyl substituted with 0-3R^(7e); R^(7d), at each occurrence, is selected from H, C₁₋₆ alkyl, C₃₋₆cycloalkyl, and phenyl; R^(7e), at each occurrence, is selected fromC₁₋₆ alkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, (CH₂)_(r)NR^(7f)R^(7f); R^(7f) is selected from H and C₁₋₆ alkyl;R⁸, at each occurrence, is selected from C₁₋₈ alkyl, (CH₂)_(r)C₃₋₆cycloalkyl, CF₃, Cl, Br, I, F, (CH₂)_(r)NR^(8f)R^(8f), NO₂, CN, OH,(CH₂)_(r)OR^(8d), and (CH₂)_(r)phenyl substituted with 0-3 R^(8e);R^(8d), at each occurrence, is selected from C₁₋₆ alkyl and phenyl;R^(8e), at each occurrence, is selected from C₁₋₆ alkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, OH, and (CH₂)_(r)OC₁₋₅ alkyl; and R^(8f), at eachoccurrence, is selected from H and C₁₋₅ alkyl.
 40. The compoundaccording to claim 15, wherein R¹⁰ is selected from F, Cl, Br, OCF₃, andCF₃.
 41. The compound according to claim 40, wherein X is unsubstitutedpropyl.
 42. The compound according to claim 40, wherein: Y is selectedfrom NR¹¹C(═NR^(a))NR¹¹, NR¹¹C(═CHCN)NR¹¹, NR¹¹C(═CHNO₂)NR¹¹, andNR¹¹C(═C(CN)₂)NR¹¹.
 43. The compound according to claim 41, wherein: Yis selected from NR¹¹C(═NR^(a))NR¹¹, NR¹¹C(═CHCN)NR¹¹,NR¹¹C(═CHNO₂)NR¹¹, and NR¹¹C(═C(CN)₂)NR¹¹.
 44. The compound according toclaim 1, wherein the compound is selected from:(±)-cis-N-{3-[4-benzyl-2-piperidinyl]propyl}-N′-(3-cyanophenyl)urea,(±)-trans-N-(3-cyanophenyl)-N′-[2-[4-(benzyl)-2-piperidinyl]ethyl]urea,(±)-trans-N{3-[4-benzyl-2-piperidinyl]propyl}-3-cyanobenzamide,(±)-trans-N-(3-acetylphenyl)-N′-[2-[4-(benzyl)-2-piperidinyl]ethyl]urea,(±)-trans-N{3-[4-benzyl-2-piperidinyl]propyl}-4-fluorobenzenesulfonamide,(±)-trans-N{3-[4-benzyl-2-piperidinyl]propyl}benzamide,(±)-cis-N-(3-cyanophenyl)-N′-[3-[4-(4-fluorobenzyl)-2-piperidinyl]propyl]urea,(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(4-fluorobenzyl)-2-piperidinyl]propyl]urea,(±)-cis-N-(3-acetylphenyl)-N′-[3-[4-(4-fluorobenzyl)-2-piperidinyl]propyl]urea,(±)-trans-N-(3-chlorophenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propyl]urea,(±)-trans-N-(phenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propyl]urea,(±)-trans-N-(3-fluorophenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propyl]urea,(±)-trans-N-(3-methoxyphenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propyl]urea,(±)-trans-N-(4-carboethoxyphenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propyl]urea,(±)-trans-N-(4-fluorophenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propyl]urea,(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propyl]urea,(±)-trans-N-(3-trifluoromethylphenyl)-N′-[3-[4-(benzyl)-2-piperidinyl]propyl]urea,(±)-cis-N-(3-cyanophenyl)-N′-[3-[4-(benzyl)-1-propyl-2-piperidinyl]propyl]urea,(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(benzyl)-1-propyl-2-piperidinyl]propyl]urea,(±)-cis-N-(3-acetylphenyl)-N′-[3-[4-(4-fluorobenzyl)-1-propyl-2-piperidinyl]propyl]urea,(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(4-fluorobenzyl)-1-propyl-2-piperidinyl]propyl]urea,(±)-trans-N-(3-cyanophenyl)-N′-[4-[4-(benzyl)-2-piperidinyl]butyl]urea,(±)-trans-N-(3-acetylphenyl)-N′-[4-[4-(benzyl)-2-piperidinyl]butyl]urea,N-(3-acetylphenyl)-N′-{[3-[2S,4S]-4-(4-fluorobenzyl)piperidinyl]propyl}urea,N-(3-acetylphenyl)-N′-{[4-[2R,4R]-4-(4-fluorobenzyl)-2-piperidinyl]butyl}urea,N-(3-cyanophenyl)-N′-{[4-[2R,4R]-4-(4-fluorobenzyl)piperidinyl]butyl}urea,N-(3-acetylphenyl)-N′-{3-[(2S,4R)-4-(2,4-difluorobenzyl)piperidinyl]propyl}urea,N-{3-[(2S,4R)-1-allyl-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3,5-diacetylphenyl)urea,N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-hydroxyethyl)piperidinyl]propyl}urea,N-{3-[(2S,4R)-1-acetyl-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3,5-diacetylphenyl)urea,N-(3,5-diacetylphenyl)-N′-{3-[(2S)-4-(4-fluorobenzyl)-1-(2-fluoroethyl)piperidinyl]propyl}urea,(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(benzyl)-1-(2-hydroxyethyl)-2-piperidinyl]propyl]urea,(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(benzyl)-1-methyl-2-piperidinyl]propyl]urea,(±)-trans-N-(3-acetylphenyl)-N′-[3-[4-(benzyl)-1-ethyl-2-piperidinyl]propyl]urea,N-(3-acetylphenyl)-N′-{[3-(2R,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,N-(3-acetylphenyl)-N′-{[3-(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,N-(3-acetylphenyl)-N′-{[3-(2S,4R)-4-(4-fluorobenzyl)1-propylpiperidinyl]propyl}urea,N-(3-acetylphenyl)-N′-{[3-(2S,4R)-4-(4-fluorobenzyl)1-methylpiperidinyl]propyl}urea,N-(3-acetylphenyl)-N′-{[3-(2S,4R)-4-(4-fluorobenzyl)-1-(2-hydroxyethyl)piperidinyl]propyl}urea,[(2S,4R)-2-(3-{[(3-acetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)piperidinyl]aceticacid,N-(3-acetylphenyl)-N′-{3-[(2S,4R)-1-benzyl-4-(4-fluorobenzyl)piperidinyl]propyl}urea,(±)-trans-N-{3-[(4-benzyl-2-piperidinyl]propyl}-N′-(3-fluoro-4-methylphenyl)urea,(±)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-N′-(3,4-dimethoxyphenyl)urea,(±)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-N′-(6-methoxy-3-pyridinyl)urea,(±)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-N′-(1H-indazol-6-yl)urea,N-(3-acetylphenyl)-N′-{3-[(2S,4R)-1-(cyclopropylmethyl)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,N-(3-cyanophenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,N-(3-cyanophenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}urea,N-(3-acetylphenyl)-N′-{3-[(2S,4R)-1-allyl-4-(4-fluorobenzyl)piperidinyl]propyl}urea,N-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea,N-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}-N′-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea,(2S,4R)-2-(3-{[(E)-{[(E)-amino(oxo)methyl]imino}(3,5-diacetylanilino)methyl]aminolpropyl)-4-(4-fluorobenzyl)-N-methyl-1-piperidinecarboxamide,N-[(E)-({3-[(2S,4R)-1-acetyl-4-(4-fluorobenzyl)piperidinyl]propylyamino)(3,5-diacetylanilino)methylidene]urea,N″-cyano-N-(3,5-diacetylphenyl)-N′-(3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-hydroxyethyl)piperidinyl]propyl}guanidine,N-(3,5-diacetylphenyl)-N′-(3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,N-(3,5-diacetylphenyl)-N′-{3-[(2S)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}urea,N-[(E)-(3,5-diacetylanilino)({3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}amino)methylidene]urea,N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}guanidine,(2S,4R)-2-(3-{[(3,5-diacetylanilino)carbonyl]aminolpropyl)-4-(4-fluorobenzyl)-1-piperidinecarboximidamide,N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propylpiperidinyl]propyl}guanidine,(2S,4S)-2-(3-{[(3-acetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)-1-piperidinecarboximidamide,N-{3-[(2S,4R)-1-(aminoacetyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3,5-diacetylphenyl)urea,N-{3-[(2S,4R)-1-allyl-4-(4-fluorobenzyl)piperidinyl]propyl}-N″-cyano-N′-(3,5-diacetylphenyl)guanidine,N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-fluoroethyl)piperidinyl]propyl}guanidine,N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-propynyl)piperidinyl]propyl}guanidine,N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-methylpiperidinyl]propyl}guanidine,N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-1-ethyl-4-(4-fluorobenzyl)piperidinyl]propyl}guanidine,N-[3,5-bis(1-methyl-1H-tetraazol-5-yl)phenyl]-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,N-{3-[(2S,4R)-1-acetyl-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-[3,5-bis(l-methyl-1H-tetraazol-5-yl)phenyl]urea,N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-1-(2,2-difluoroethyl)-4-(4-fluorobenzyl)piperidinyl]propyl}urea,N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(methylsulfonyl)piperidinyl]propyl}urea,N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-propionylpiperidinyl]propyl}urea,N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-isobutyrylpiperidinyl]propyl}urea,(2S,4R)-2-(3-{[(3,5-diacetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)-N-methyl-1-piperidinecarboxamide,(2S,4R)-2-(3-{[(3,5-diacetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)-1-piperidinecarboxamide,N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-pyridinylmethyl)piperidinyl]propyl}urea,2-[(2S,4R)-2-(3-{[(3,5-diacetylanilino)carbonyl]amino}propyl)-4-(4-fluorobenzyl)piperidinyl]acetamide,N-{3-[(2S,4R)-1-[(2S)-2-aminopropanoyl]-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3,5-diacetylphenyl)urea,N-{3-[(2S,4R)-1-[(2R)-2-aminopropanoyl]-4-(4-fluorobenzyl)piperidinyl]propyl}-N′-(3,5-diacetylphenyl)urea,N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-propynyl)piperidinyl]propyl}urea,1-(3-{[(E)-1-({3-[(2S)-4-(4-fluorobenzyl)piperidinyl]propyl}amino)-2-nitroethenyl]amino}phenyl)ethanone,(±)-trans-N-(3-[4-(benzyl)-2-piperidinyl]propyl}-N′-[3-(phenylsulfonyl)phenyl]urea,(±)-trans-N-{3-[4-(benzyl)-2-piperidinyl]propyl}-N′-[3-chloro-4-(diethylamino)phenyl]urea,(±)-trans-N-(3-{[({3-[4-benzyl-2-piperidinyl]propyl}amino)carbonyl]amino}phenyl)acetamide,(±)-trans-N-{3-[4-benzylpiperidinyl]-2-propyl}-N′-[3-(1-hydroxyethyl)phenyl]urea,(±)-trans-dimethyl5-{[({3-[4-benzyl-2-piperidinyl]propyl}amino)carbonyl]amino}isophthalate,(±)-trans-ethyl3-{[({3-[4-benzyl-2-piperidinyl]propyl}amino)carbonyl]amino}benzoate,(±)-trans-N-{3-[4-benzyl-2-piperidinyl]propyl}-N′-(3-chlorophenyl)urea,N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-oxo-propyl)piperidinyl]propyl}urea,N-[3-(2-{3-[(3,5-diacetylanilinocarbonyl)amino}propyl}-4-(4-fluorobenzyl)-1-piperidinyl)propyl]acetamide,N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(3-hydroxypropyl)piperidinyl]propyl}urea,N″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(2-oxo-propyl)piperidinyl]propyl}guanidine,andN″-cyano-N-(3,5-diacetylphenyl)-N′-{3-[(2S,4R)-4-(4-fluorobenzyl)-1-(3-hydroxypropyl)piperidinyl]propyl}guanidine.45. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 46.A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound accordingto claim 22, or a pharmaceutically acceptable salt thereof.
 47. A methodfor modulation of CCR3 receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of claim 1.48. The method of claim 47 wherein modulation of CCR3 receptor activitycomprises contacting a CCR3 receptor with an effective inhibitory amountof the compound.
 49. A method for treating inflammatory disorders whichare at least partially mediated by CCR-3 comprising administering to apatient in need thereof a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 50.A method according to claim 49, wherein the disorder is selected fromasthma, allergic rhinitis, atopic dermatitis, inflammatory boweldiseases, idiopathic pulmonary fibrosis, bullous pemphigoid, allergiccolitis, eczema, conjunctivitis, familial eosinophilia, eosinophiliccellulitis, eosinophilic pneumonias, eosinophilic fasciitis, andeosinophilic gastroenteritis.
 51. The method according to claim 50,wherein the disorder is selected from asthma, allergic rhinitis, atopicdermatitis, and inflammatory bowel diseases.
 52. The method according toclaim 51, wherein the disorder is asthma.
 53. The method according toclaim 51, wherein the disorder is allergic rhinitis.
 54. The methodaccording to claim 51, wherein the disorder is atopic dermatitis. 55.The method according to claim 51, wherein the disorder is inflammatorybowel diseases.
 56. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound according to claim 12, or a pharmaceuticallyacceptable salt thereof.
 57. A method for treating inflammatorydisorders which are at least partially mediated by CCR3 comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 12, or a pharmaceuticallyacceptable salt thereof.
 58. A method according to claim 57, wherein thedisorder is selected from asthma, allergic rhinitis, atopic dermatitis,inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullouspemphigoid, allergic colitis, eczema, conjunctivitis, familialeosinophilia, eosinophilic cellulitis, eosinophilic pneumonias,eosinophilic fasciitis, eosinophilic gastroenteritis.
 59. The methodaccording to claim 50, wherein the disorder is selected from asthma,allergic rhinitis, atopic dermatitis, and inflammatory bowel diseases.